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Background: Incidences of pediatric malignancies are increasing. In management of various childhood malignancies like hematological, bone and soft tissue tumors radiotherapy plays a crucial role. RT treatment planning and delivery poses a challenge to clinicians. Hence with this study we wanted to know the radiotherapy practices in our institution. Materials and Methods: This was a retrospective study analyzing case records and RT charts of all pediatric malignancies who received radiation treatment for a period of 3 years from January 2018 to December 2021. Demographic details, RT details, toxicity details were carefully recorded. Results: Details of 73 pediatric malignancy cases who received RT were analyzed. Median age was 10 years and the majority were males (66%). Commonest malignancies which received RT treatment were ALL (30%), Brain tumors (26%) and bone and soft tissue tumors (22%). Radiotherapy was given as a part of radical intent treatment including neo adjuvant, definitive, adjuvant and prophylactic in 92% of patients. Conformal RT techniques in the form of 3DCRT and VMAT were used in majority (91%) cases. A significant proportion (27%) of cases required anesthesia for RT treatment delivery. 16% of patients had treatment break and common reasons for treatment break being infections (COVID, respiratory) and neutropenia. Grade 3 or more acute toxicities were observed in 14% of patients and hematological toxicity was the most frequent. Conclusion: Hematological and bone & soft tissue tumors are the most common pediatric malignancies requiring RT as a part of multimodality treatment. For RT treatment delivery anesthesia services may be required in pediatric malignancies. Acute Grade 3 or more toxicities and treatment breaks are a concern and these pediatric cases require a properly coordinated supportive care during treatment.

Identification of patients with a low grade glioma with a long-term recurrence-free survival is of clinical value as radiotherapy can be postponed until recurrence. The recurring glioma may increase in malignancy compared to the original tumor, which is possibly related to radiotherapy. We studied proliferation by counting mitotic figures and by MIB-1 labeling, apoptosis by TUNEL and expression of proteins related to cell cycle regulation by immunohistochemical analysis of p53, p21, bcl-2 and bax expression in 48 low grade gliomas. Astrocytomas (A, n = 14) and oligodendrogliomas (O, n = 4) with a recurrence-free survival of more than 9 years after surgery had a signficantly lower p53 index compared to A (n = 18) and O (n = 12) with a histopathologically documented recurrence. Additionally, the recurrence-free A had a higher p21 index. No significant differences were observed in MIB-LI, TUNEL-LI, bcl-2 and bax expression. Initially low grade gliomas and their corresponding recurrences were compared (n = 30). In the gliomas without radiotherapy (n = 15), no differences in mitotic rate, TUNEL-LI, p53, p21, bcl-2 and bax expression were found between primary tumors and their recurrences. Only MIB-LI was higher in the recurrent tumors. In the gliomas with radiotherapy (n = 15) no differences were detected in these parameters between the original tumor and the recurrent tumor except for a higher number of mitoses in the recurrent tumors. We conclude that low grade gliomas with a long-term recurrence-free survival were characterized by a low p53 protein expression and, in the case of A, a higher p21 index. We found no evidence that radiotherapy is involved in changes of proliferation, apoptosis or expression of proteins related to cell cycle regulation in recurring gliomas.

In this study we examined the efficacy of cryopreserving porcine fetal mesencephalic tissue. After microscopical dissection of the ventral mesencephalon (VM) from E28 pig fetuses, the collection of explants was randomly divided into two equal parts. One part was directly prepared as cell suspension. The other part was stored in hibernation medium for less than 2 days and then cryopreserved as tissue fragments and stored in liquid nitrogen. After 2 weeks up to 1 year, these tissue fragments were thawed and processed as cell suspensions. After cell counting and assessment of viability, these cell suspensions were used to examine survival, morphology, and neurite formation of the dopaminergic neurons in cell culture as well as after intrastriatal implantation in 6-OHDA-lesioned rats. Comparison of cryopreserved with fresh VM cell suspensions showed no significant difference with respect to cell viability and the average number of living cells per VM explant. The morphology of cultured dopaminergic neurons after cryopreservation was identical to that of fresh cells. After intrastriatal implantation, survival and outgrowth of cryopreserved dopaminergic neurons as well as functional effects did not differ from those of fresh cells. In conclusion, the cryopreservation technique we used proves to be a reliably effective method for storing porcine fetal VM tissue.

We investigated whether left-hemisphere arachnoid cysts lead to reorganization of the language function using PET. A group analysis demonstrated that patients showed no more right-hemisphere activation than a matched control group. Several patients had clear language localizations in the left hemisphere during language comprehension; none of the patients showed right-hemisphere activation. We conclude that left-hemisphere tissue must suffer considerable compromise before reorganization of language into the right hemisphere becomes necessary. Language activations within the left hemisphere are clearly displaced. This is consistent with mere physical displacement in some patients rather than reorganization within the left hemisphere; in others intrahemispheric reorganization cannot be excluded.

Chemical analysis of brain tumour cyst contents has invalidated the concept of cyst formation being the result of tumour necrosis, and a common mechanism of vasogenic brain oedema and cyst formation, namely blood-brain barrier (BBB) disruption, has been suggested. To analyse a possible relationship between the occurrence of vasogenic oedema and the presence of cysts, we performed a volumetric analysis on the MRI and CT studies of 60 patients with primary or metastatic brain tumours. We compared four groups of tumours: 30 gliomas, of which 15 were cystic and 15 not and 30 metastatic brain tumours of which 15 were cystic and 15 not. Although the mean volume of oedema was similar for cystic and noncystic tumours, the ratio of oedema to tumour volume was approximately four times as high in cystic supratentorial tumours. This would support the view that cyst formation may be related to relatively greater production of oedema, possibly due to fusion of microcysts containing oedema fluid. The ratio of oedema to tumour volume is not greater in cystic cerebellar and intraventricular tumours. This may be due to the different anatomical organization of the cerebellar white matter, and the fact that the intraventricular tumours are bordered by subcortical grey matter. In these cases, spread of oedema is impeded. Formation of a large amount of brain oedema is therefore not an essential prerequisite for cyst formation.

Human fetal ventral mesencephalon tissue has been used as dopaminergic striatal implants in Parkinsonian patients, so far with variable effects. Fetuses from animals that breed in large litters, e.g., pigs, have been considered as alternative donors of dopaminergic tissue. The optimal gestational age of the porcine fetal donors has not been studied systematically. We collected ventral mesencephalic (VM) tissue from fetal pigs, embryonal ages E21, E28, E42, and E70, and examined the viability of the fetal VM cells after dissociation, the expression of tyrosine hydroxylase (TH) in culture, the presence of catecholamines, and the cellular survival and outgrowth up to 10 months after intrastriatal implantation in rats. The highest viability was found in suspensions prepared from E28 fetuses. The highest number of TH-positive cells was found in cell cultures prepared from E28 VM tissue. Explants with a gestational age of 28 and 42 days contained the largest amount of dopamine. Only E28-derived grafts showed TH-cell survival after implantation in rat striatum. Our results show that a gestational age of 28 days must be considered to be the optimal age for dopaminergic tissue derived from pig fetuses for therapeutic use as intrastriatal grafts in Parkinsonian patients.

Background: In the preoperative diagnosis of malignant brain tumours there is often uncertainty regarding their metastatic or primary nature, requiring dissemination studies. Currently FDG-wbPET is being used for the efficient detection of systemic tumours. It therefore may become a substitute for the conventional dissemination studies if it allows an earlier diagnosis., Method: In this descriptive and preliminary study a population of 14 patients with suspected or proven metastatic lesions, [18F]-fluoro-2-deoxy-D-glucose whole body positron emission tomography (FDG-wbPET) was conducted and verified by additional conventional dissemination studies. FINDINGS AND THEIR INTERPRETATION: The entire series of dissemination studies required an average of 30 days with a range of 4-73 days. The FDG-wbPET was corroborated by the other dissemination studies in 10 of the 14 patients. In 7 of these 10 patients both PET and dissemination studies showed systemic abnormal findings, but in one case the presence of high pulmonary activity on the FDG-wbPET and the abnormal findings on the chest X-rays proved to be Aspergillus infection at autopsy. In the other 2 cases the negative PET findings corresponded to the absence of systemic dissemination. In 5 cases there was disagreement of the results of the FDG-wbPET with other evidence, among which there were 2 cases of glioblastoma in which systemic metastases were most unlikely, and the foci of activity on the FDG-wbPET had to be considered as false positives. In the remaining 3 cases the systemic presence of high activity on the FDG-wbPET indicated the systemic presence of tumour, whereas the other dissemination studies disclosed no tumour., Conclusion: The results warrant the use of FDG-wbPET as a screening method for the search of metastases, allowing other studies to be focussed on the lesion. But from the cost/benefit point of view this would make the method less suitable as a substitute for dissemination studies in general, although it may speed up the diagnostic process.

With the introduction of new (immuno-)histochemical techniques it is now possible to assess rates of proliferation and apoptosis in brain gliomas using archival paraffin embedded material. As proliferation and apoptosis are related to tumour growth rate quantification of these processes has prognostic value and is related to tumour grading. In this study we assessed the proliferation rate by measuring the Ki-67 labelling index using the MIB-1 antibody (MIB-LI) and the apoptotic rate using the in situ labelling of DNA strand breaks with TUNEL (TUNEL-LI) in 315 supratentorial gliomas. MIB-LI and TUNEL-LI in astrocytomas (A) where significantly lower compared to anaplastic astrocytomas (AA), glioblastomas (GBM) and oligodendroglial tumours [oligodendrogliomas (O) and anaplastic oligodendrogliomas (AO)]. MIB-LI and TUNEL-LI were significantly lower in AA compared to GBM. In astrocytic tumours MIB-LI and TUNEL-LI appeared to be correlated. As the distinction between A and AA is of clinical value but can be difficult histomorphologically we analysed the prognostic value of MIB-LI and TUNEL-LI in gliomas with particular emphasis on A and AA. MIB-LI below 10% was of prognostic value in A and AA, O and AO but not in GBM on univariate survival analysis. TUNEL-LI was of no prognostic value. With multivariate survival analysis MIB-LI lost prognostic significance in O and AO. Astrocytomas with a gemistocytic component (AG) are similar to A with respect to survival and MIB-LI and TUNEL-LI. MIB-LI is of independent prognostic value in A and AA. Assessment of MIB-LI in A and AA can be used as an aid in distinguishing A and AA.

We examined the mechanism of cyst formation in extra-axial tumours in the central nervous system (CNS). Cyst fluid, cerebrospinal fluid (CSF) and blood plasma were analysed in eight patients with nine peritumoral cysts: four with meningiomas, two with intracranial and two spinal intradural schwannomas. Measuring concentrations of various proteins [albumin, immunoglobulin G (IgG), IgA, alpha 2-macroglobulin and IgM] in cyst fluid, CSF and blood plasma provides insight into the state of the semipermeability of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier. Peritumoral cysts accompanying intra-axial brain tumours are the end result of disruption of the BBB and oedema formation. Unlike intra-axial tumours which lie embedded within nervous tissue, extra-axial tumours tend to be separated from nervous tissue by arachnoid and pia mater. High concentrations of proteins were measured in the cyst fluid, approaching blood plasma levels, suggesting a local barrier disruption, and passage across the arachnoid, pia mater and cortical/medullary layer into the CNS parenchyma, leaving the protein concentrations of CSF practically unchanged. We confirmed that very high concentrations of protein are to be found in tumour cysts, plasma proteins forming almost 90% of the total protein in the cyst. We review current hypotheses on the pathogenesis of cysts accompanying neoplasms, particularly meningiomas and schwannomas, and conclude that the majority of proteins in cyst fluid in extra-axial, intradural meningiomas and schwannomas are plasma proteins. This provides a strong argument for pathogenesis of extra-axial intradural tumour cysts in favour of leakage of plasma proteins out of the tumour vessels into the nervous tissue.

Recent reports have suggested that cyst formation accompanying astrocytomas in the central nervous system (CNS) is due to an edematous process caused by blood-brain barrier (BBB) disruption and not a result of necrosis. This study is performed to investigate whether the hypothesis of cyst formation based on BBB disruption also applies to various pathologically different intra-axial gliomatous tumors and metastases. By chemical analysis, using immunokinetic nephelometry, isoelectric focussing, cellulose acetate electrophoresis and a biuretic method, the concentrations of albumin, immunoglobulin G (IgG), IgA, alpha2-macroglobulin, IgM and total protein were measured and proportions of concentrations of these proteins were compared in cyst fluid, blood plasma and cerebrospinal fluid (CSF). Our data, based on the chemical analysis of cyst fluid and blood plasma of 37 patients, including 2 ependymomas (one cerebral; one thoracic), 3 oligodendrogliomas, 4 hemangioblastomas, 5 cerebellar astrocytomas and 1 cervical, 1 giant astrocytoma grade one, 1 gangliocytoma, 1 neuroblastoma and 19 metastases (five lung-; two renal-; three breast-; one melanoma-; one thyroid metastasis and seven metastases of unknown origin) present high protein concentrations in the cysts with a highly similar spectrum of proteins in the tumor cyst fluid and blood plasma, suggesting a BBB disruption followed by exudation of plasma proteins into the brain parenchyma with formation of edema and transition of edematous tissue into a cyst accompanying the tumor. Although histopathologically different types of tumor tissue are involved, data suggests that the pathogenesis of cysts accompanying gliomatous tumors and metastases in the CNS is based on BBB disruption and consequent edema, as is the case in the formation of cysts in anaplastic astrocytomas.

We monitored 10 patients with unresected (9) or partially resected (1) supratentorial gliomas with 11C-tyrosine position emission tomography (TYR-PET) before and after radiotherapy. TYR-PET tumour volumes were measured using a threshold technique. In seven patients the tumour volume decreased after radiotherapy, although all gliomas persisted on TYR-PET images. In eight patients the tumour protein synthesis rate (PSR) was calculated using a dynamic study protocol in combination with a PATLAK analysis. There were no changes in PSR after radiotherapy, but the PSR was calculated on the remaining tumour volume using the same threshold technique as before therapy, i.e. the decrease in tumour volume was not taken into account. In eight patients the PET data were compared with magnetic resonance spectroscopic imaging (1H-MRSI) performed simultaneously. Although there was no statistically significant correlation between TYR-PET volume changes and 1H-MRSI choline level we observed a simultaneous decrease in volume and choline in four patients.

Colloid cysts of the third ventricle have been investigated by chemical characterization of the cyst contents using ELISA with monoclonal antibodies for certain carbohydrate epitopes as well as a polyclonal antiserum against peptide domains, and immunohistochemistry on the cyst wall using the same antibodies. Furthermore, the carbohydrate composition of one sample has been determined after gel filtration. The cyst contents reacted strongly with the monoclonal antibody for the sulfo-Lewis epitope, and with the antimucin polyclonal antiserum. In one case the cyst fluid exhibited a blood group A antigen. A sample of cyst wall obtained by biopsy showed strong immunoreactivity against sulfo-Lewis antigen, and the sialo-Lewis antigen. The presence of the S atom with its high atomic number relative to that of C, H, and O atoms, may contribute to the high density appearance of colloid cysts on CT-scans. The sulfo-Lewis and sialo-Lewis carbohydrate epitopes are known as ligands for selectins, involved in inflammatory processes, and may well account for the aseptic meningeal reaction that may follow spilling of cyst contents during operative evacuation. The carbohydrate epitopes exhibited by colloid cysts and their contents, have also been reported for the mucins of salivary glands, uterine cervix, gall bladder and colon, and therefore, are not inconsistent with the assumption of an endodermal origin of colloid cysts.

There is a growing interest in cystic lesions of the brain. By examining the cyst content of brain tumours more insight into the pathogenesis of cyst formation has been found. In this study, 39 samples of cyst fluid of 34 patients with a cyst accompanying a brain tumour were collected and studied biochemically regarding their protein content, lactate and pH. In this study we investigated the relation between the grade of malignancy and the lactate-concentration and the discrepancy between the high levels of lactate in cysts and their alkaline environment. The results of the measurements of the concentrations of albumin, immunoglobulines (IgG, IgA, IgM) and alpha 2-macroglobulin in cysts compared to those in sera suggest that cyst formation associated with tumour is based upon a disruption of the blood-brain barrier with exudation of plasma proteins into the brain parenchyma resulting in accumulation of fluid (oedema) and eventually in formation of a cyst. There appears to be a positive relation between the grade of malignancy and the concentration of lactate in the cysts with a significant 2-fold increase in lactate concentration in malignant tumour cysts compared to the more benign tumour cysts (p < 0.001) probably on account of aerobic glycolysis with production of lactate by the tumour. The measured pH values in the cysts were above normal, resulting in a discrepancy of the high levels of lactate in the cyst with the alkaline environment and this suggests efflux of H(+)-ions by a Na/H exchange mechanism to compensate for the change of pH.

We determined dopamine (DA), noradrenaline (NA), and adrenaline (A), as well as immunohistochemically stained tyrosine hydroxylase (TH) and DA in dissected rat ventral mesencephalon (VM) tissue from Embryonic Day (ED) 14 to Postnatal Day (P) 17. Whole VM tissue DA, NA, and A contents increased with advancing age. VM DA/protein increased from ED15 to ED16, whereas NA/protein increased from ED15 to ED16 and from ED20 to P4. VM DA/NA ratio increased from ED14 to ED15 and decreased from ED18 to P4. VM cell suspensions exhibited higher DA/NA ratios than whole VM tissue. Washed cell suspensions had higher DA/NA than unwashed counterparts. We conclude that data from both VM immunohistochemistry and catecholamine assays relate to VM development. VM DA is contained mainly in cells, whereas VM NA is located in fibers that channel at the dorsal side of the VM. Determination of tissue catecholamine contents may be helpful for the biochemical characterization of tentatively identified VM grafts.

Using in vivo proton-magnetic resonance spectroscopy (1H-MRS), which allows the measurement of metabolites of adequate tissue concentration, the origin of lactate in peritumoral edema has been assessed by comparison with lactate levels in the central and marginal areas of the tumor in 18 patients with cerebral gliomas. In the majority of cases lactate content in the area of peritumoral edema was lower than that in the tumor margin or tumor center, which is consistent with the assumption that the tumor is the source of lactate, which then reaches the surrounding area of edema by diffusion. In 3 of the 18 cases the amount of lactate in the peritumoral edematous tissue was higher than in the tumor, indicating that the lactate is locally produced on account of ischemia due to regional elevation of tissue pressure in the edematous area.

The physicochemical properties of water enable it to act as a solvent for electrolytes, and to influence the molecular configuration and hence the function--enzymatic in particular--of polypeptide chains in biological systems. The association of water with electrolytes determines the osmotic regulation of cell volume and allows the establishment of the transmembrane ion concentration gradients that underlie nerve excitation and impulse conduction. Fluid in the central nervous system is distributed in the intracellular and extracellular spaces (ICS, ECS) of the brain parenchyma, the cerebrospinal fluid, and the vascular compartment--the brain capillaries and small arteries and veins. Regulated exchange of fluid between these various compartments occurs at the blood-brain barrier (BBB), and at the ventricular ependyma and choroid plexus, and, on the brain surface, at the pia mater. The normal BBB is relatively permeable to water, but considerably less so to ions, including the principal electrolytes Brain fluid regulation takes place within the context of systemic fluid volume control, which depends on the mutual interaction of osmo-, volume-, and pressure-receptors in the hypothalamus, heart and kidney, hormones such as vasopressin, renin-angiotensin, aldosterone, atriopeptins, and digitalis-like immunoreactive substance, and their respective sites of action. Evidence for specific transport capabilities of the cerebral capillary endothelium, for example high Na+K(+)-ATPase activity and the presence at the abluminal surface of a Na(+)--H+ antiporter, suggests that cerebral microvessels play a more active part in brain volume regulation and ion homoeostasis than do capillaries in other vascular beds. The normal brain ECS amounts to 12-19% of brain volume, and is markedly reduced in anoxia, ischaemia, metabolic poisoning, spreading depression, and conventional procedures for histological fixation. The asymmetrical distributions of Na+ K+ and Ca2+ between ICS and ECS underlie the roles of these cations in nerve excitation and conduction, and in signal transduction. The relatively large volume of the CSF, and extensive diffusional exchange of many substances between brain ECS and CSF, augment the ion-homeostasing capacity of the ECS. The choroid plexus, in addition to secreting CSF principally by biochemical mechanisms (there is an additional small component from the extracellular fluid), actively transports some substances from the blood (e.g. nucleotides and ascorbic acid), and actively removes others from the CSF. In contrast with CSF secretion, CSF reabsorption is principally a biomechanical process, passively dependent on the CSF-dural sinus pressure gradient. Pathological increases in intracranial water content imply development of an intracranial mass lesion. The additional water may be distributed diffusely within the brain parenchyma as brain oedema, as a cyst, or as increase in ventricular volume due to hydrocephalus. Brain oedema is classified on the basis of pathophysiology into four categories, vasogenic, cytotoxic, osmotic and hydrostatic. The clinical conditions in which brain oedema presents the greatest problems are tumour, ischaemia, and head injury. Peritumoural oedema is predominantly vasogenic and related to BBB dysfunction. Ischaemic oedema is initially cytotoxic, with a shift of Na+ and CI- ions from ECS to ICS, followed by osmotically obliged water, this shift can be detected by diffusion-weighted MRI. Later in the evolution of an ischaemic lesion the oedema becomes vasogenic, with disruption of the BBB. Recent imaging studies in patients with head injury suggest that the development of traumatic brain oedema may follow a biphasic time course similar to that of ischaemic oedema. Hydrocephalus is associated in the great majority of cases with an obstruction to the circulation or drainage of CSF, or, occasionally, with overproduction of CSF by a choroid plexus papilloma. In either case, the consequence is a ris

During cold preservation for transplantation the tissue hydration state changes. It is not known whether such changes lead to altered relaxation times of 31P nuclei with potential consequences for the quantification of tissue metabolites. Therefore, 31P spectroscopic and proton T1 relaxometric measurements were performed on 42 isolated human donor livers shortly before implantation. The results demonstrate that 31P T1 relaxation times change during preservation for clinical transplantation, thus quantification of tissue metabolites in cold stored donor livers may be in part dependent on the tissue hydration state. Furthermore, it appeared that changes in tissue hydration state especially affect the physico-chemical characteristics of the intracellular fluid compartment. This study indicates that reliable spectroscopic quantification of tissue metabolites, particularly during sequential spectroscopic measurements in cold stored donor organs is best warranted under fully relaxed conditions.

We report 2 cases of arachnoid cysts, one with a retrocerebellar and the other with a left temporal localization, in which immunohistochemical studies had been conducted. The results of the immunohistochemistry on the presence of carcino-embryonic antigen (CEA) and glial fibrillary acidic protein (GFAP), and of the scanning- and transmission electron microscopy revealed the cyst lining to be identical to subdural neurothelium. Progesterone receptors were found in the nuclei of cells lining the cyst, which also suggests the similarity of the cyst lining to arachnoid granulations and meningiomas as derivatives of subdural neurothelium, which also possess progesterone receptors.

Brain tissue of rats pretreated with methylprednisolone or with the 21-aminosteroid U74389F, and that of untreated control rats, was assessed for the expression of Annexin-1 (Anx-1) and the transcription of its mRNA. For this purpose Anx-1 cDNA was amplified and simultaneously a T7-RNA-polymerase promotor was incorporated into the cDNA using Polymerase Chain Reaction (PCR). Then digoxigenin-11-UTP was incorporated into the transcribed cRNA with T7-RNA-polymerase. With this probe in situ hybridization was carried out in sections of the brain. The probe was visualized by an immunoassay using an anti-digoxigenin antibody conjugate. Anx-1 protein was assessed by means of immunohistochemistry using a polyclonal antibody. The various brain areas of the control animals showed an appreciable amount of Anx-1 at mRNA or protein level; on the other hand, the animals which had been pretreated with either steroid, showed a more intense Anx-1 mRNA signal than the controls in many areas. In the pretreated animals Anx-1 immunostaining was unchanged in cortex, basal ganglia, amygdala and septum, but more intense in hippocampus, hypothalamus and thalamus. In ependyma, choroid plexus, meninges, and vascular walls there was no Anx-1 mRNA transcription detectable. An opposite profile was shown by the Anx-1 immunoreactivity, the protein was present in control animals as well as the steroid-pretreated animals, suggesting that here the protein was either from systemic origin, or has diffused from adjacent structures. The results indicate that Anx-1 mRNA transcription is upregulated by either steroid, and that in the untreated animals there is a resting level of Anx-1 mRNA transcription, presumably reflecting physiological influences on Anx-1 expression.

Brain tissue of rats pretreated with methylprednisolone or with the 21-aminosteroid U74389F, and that of untreated control rats, was assessed for the expression of annexin-1 (Anx-1) and the transcription of its mRNA. For this purpose Anx-1 cDNA was amplified and simultaneously a T7-RNA-polymerase promoter was incorporated into the cDNA using a polymerase chain reaction (PCR). Then digoxigenin-11-UTP was incorporated into the transcribed cRNA with T7-RNA-polymerase. With this probe in situ hybridization was carried out on sections of the brain. The probe was visualized by an immunoassay using an antidigoxigenin antibody conjugate. Anx-1 protein was assessed by means of immunohistochemistry using a polyclonal antibody. The various brain areas of the control animals showed an appreciable amount of Anx-1 at mRNA or protein level; on the other hand, the animals which had been pretreated with either steroid, showed a more intense Anx-1 mRNA signal than the controls in many areas. In the pretreated animals Anx-1 immunostaining was unchanged in cortex, basal ganglia, amygdala and septum, but more intense in hippocampus, hypothalamus and thalamus. In ependyma, choroid plexus, meninges, and vascular walls there was no Anx-1 mRNA transcription detectable. An opposite profile was shown by the Anx-1 immunoreactivity, the protein was present in control animals as well as the steroid-pretreated animals, suggesting that here the protein was either from systemic origin, or has diffused from adjacent structures. The results indicated that Anx-1 mRNA transcription is upregulated by either steroid, and that in the untreated animals there is a resting level of Anx-1 mRNA transcription, presumably reflecting physiological influences on Anx-1 expression.

For the synthesis of [18F]Fluoro-Org 6141 via a nucleophilic substitution reaction with 18F-, the tosyl group was chosen as the leaving group because of its stability and excellent leaving group ability. The biodistribution of the high affinity and moderate lipophilicity (log P = 2.66, calculated value) ligand [18F]Fluoro-Org 6141 (specific activity 8.2 to 37 TBq/mmol, yield 10% at EOB) was examined in sham adrenalectomized (sADX) and adrenalectomized (ADX) male Wistar rats. Two days after ADX or sADX, the animals were anesthetized and 0.37 to 1.85 MBq of [18F]Fluoro-Org 6141 was administered intravenously. Kinetics of 18F activity uptake were monitored for 3 h using a stationary double-headed positron emission tomography (PET) camera, and the biodistribution was assessed by ex vivo determination of radioactivity in several tissues and different brain areas. One hour after injection of the radioligand, the bladder, kidney, liver, trachea, and bone of sADX animals contained more concentration on a wet weight basis than blood. Three hours post injection, radioactivity was retained in bladder, trachea, and bone. The accumulation of radioactivity in brain corresponded to the concentration of activity in the blood within the first hours after injection. ADX animals showed a higher uptake of 18F activity in spleen, testes, and brain areas (hippocampus and brainstem) but a lower uptake in bone than sADX rats. PET scans suggested that 18F activity uptake in the brain had not yet reached a maximum at this interval. Although [18F]Fluoro-Org 6141 is not useful for PET studies of glucocorticoid receptors (GRs), the results obtained with this compound indicate a synthetic strategy suitable for the synthesis of high-affinity radioligands for GRs.

Purpose: Positron emission tomography (PET) with the amino acid tracer L-[1-C-11]-tyrosine was evaluated in 27 patients with primary and recurrent brain tumors., Materials and Methods: Patients underwent either static (n = 14) or dynamic PET (n = 13), with quantification of protein synthesis rate (PSR) and tumor-to-background ratio. Findings were compared with histologic findings., Results: Primary brain tumor was proved in 22 patients histologically, as well as metastatic cancer of unknown origin, primary non-Hodgkin lymphoma, meningioma, atypical infarction, and vasculitis in one patient each. At PET, 20 of 22 primary tumors, the metastasis, and non-Hodgkin lymphoma were correctly depicted. A false-positive finding was obtained with the infarction, and the meningioma and vasculitis were not depicted. The calculated sensitivity was 92%; specificity, 67%; and accuracy, 89%. There were no statistically significant relationships between histologic findings, PSR, and tumor-to-background ratio., Conclusion: L-[1-C-11]-tyrosine is a valid tracer for diagnosis of brain tumors and allowed quantification of PSR.

In 32 patients with gliomas, one- and two-dimensional proton magnetic resonance spectroscopy (1H-MRS) has been conducted, the latter allowing reconstruction of spectroscopic data into a spectroscopic image (MRSI), showing the distribution of the various metabolite concentrations over the cross-sectional plane. For lack of absolute concentrations, the measured concentrations of phosphocholine (CHOL), N-acetyl-L-aspartate (NAA), and lactate (LAC) were conventionally expressed in ratios relative to that of creatine (CREAT). Compared to normal brain tissue, an increased CHOL/CREAT ratio was found in all groups of tumours, in glioblastomas, high-, middle- and low-grade astrocytomas both at the margin and the core of the tumours, but in oligodendrogliomas only at the margin. This is consistent with an increased phosphocholine turnover in relation to membrane biosynthesis by the proliferating cells. The NAA/CREAT ratio was decreased in all groups of tumours, both in the centre and at the margin, reflecting replacement of functioning neurons by neoplastic cells. The LAC/CREAT ratio was elevated in the core of malignant gliomas, which may be the result of a prevailing glycolysis, characteristic of tumours, possibly in conjunction with hypoxia/ischaemia. In the perifocal oedema, there was neither elevation of the CHOL/CREAT ratio nor decrease of the NAA/CREAT ratio; an increased LAC/CREAT ratio therefore rather reflected ischaemia/hypoxia probably due to locally elevated pressure and compromised regional perfusion. In the normal brain, the metabolite ratios of grey matter did not differ from those of white matter. The frontal lobe and basal ganglia showed lower NAA/CREAT ratios than the other cerebral areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: The applicability of protein synthesis rate (PSR) determination with L-[1-11C]tyrosine (11C-TYR) and PET was assessed in patients suspected of a primary or recurrent brain tumor., Methods: Simultaneous to intravenous injection of 265 MBq of 11C-TYR, dynamic PET acquisition was started and continued for 50 min. Arterial samples were taken and analyzed for 11C-TYR and metabolites. Based on this data, a model was proposed and the corresponding PSR calculated., Results: Plasma metabolites were 11CO2, 11C-proteins and 11C-L-DOPA, constituting more than 50% of total plasma radioactivity at 40 min postinjection. Plasma 11CO2 reached a plateau of around 25% of total plasma radioactivity at 20 min postinjection. Plasma 11C-protein was not detected before 10 min postinjection, but increased exponentially afterwards to 20% at 40 min postinjection. Plasma 11C-L-DOPA was the only acid-soluble radioactive metabolite detected and was less than 8% at 40 min postinjection. Using a five-compartment model, it was shown that while the net PSR was dependent on the recycling of amino acids from protein, the amino acid incorporation was not, which was thus used for subsequent analysis. It was found that our curve-fitting results were unreliable due to the exchange of 11C-TYR between plasma and erythrocytes whereas the graphical Patlak-Gjedde analysis is hardly influenced by this transport phenomenon. The average amino acid incorporation rate thus calculated was 0.7 nmole/ml.min for nontumor tissue with a tumor versus nontumor average ratio of 1.7., Conclusion: The assessment of the PSR with TYR-PET is valuable and relatively simple to implement clinically.

The familial occurrence of gliomas, in the absence of well-defined neurological tumor syndromes such as the neurofibromatoses, is uncommon. We present a family of ten children in which the four eldest suffered from gliomas. Three of these siblings had histologically verified glioblastoma multiforme, and one patient also had an intestinal non-Hodgkin's lymphoma, but there were no stigmata or family history of a neurological tumor syndrome. Cytogenetic studies of the proband revealed a normal karyotype. Molecular genetic analysis of the proband's glioblastoma revealed two mutations in the p53 tumor suppressor gene, but these were not present in the germline DNA, mutations were not detected in the MTS1 gene in the tumors or in the germline DNA. These findings suggest that a genetic factor may be responsible for the clustering of glial tumors in this family, but it is unlikely that the genetic alteration is mutation of the p53 gene. The data are discussed in light of the literature on familial brain tumors.

A survey is given of the principles underlying the diagnosis of brain tumours. Traditionally diagnosis and localization of brain tumours have been based upon morphological criteria. Currently unsurpassed levels in imaging of anatomical details and topographical relations by the techniques of computed tomography (CT) and magnetic resonance imaging (MRI) have been achieved. The techniques of positron emission tomography (PET) and of magnetic resonance spectroscopy (MRS), which depict also metabolic and blood flow aspects, provide a refinement of our knowledge on the metabolism, structure and pathophysiological relations of a tumour to the surrounding parenchyma. Recent advances in the recording of function-related changes of the cerebral electro-magnetic field allow a better definition of critical functional areas.

Progesterone receptors (PR) were identified with an enzyme immunoassay in cytosols from human arachnoid granulations and arachnoid cysts. Meningiomas presumably originate from subdural endothelium which is abundantly present in these structures. In the three cases studied, oestrogen receptors were absent. The presence of PR in subdural endothelium may provide further ground for the expression of PR in meningiomas.

The objective of this study was to develop an optimal dissection procedure for fetal porcine ventral mesencephalon (VM) grafts and to characterize the cellular composition of such an explant, in particular with respect to the dopaminergic and GABAergic components. We have used a monolayer cell culture system to study and identify the various VM cell types. The in vitro development of the fetal VM cells and the effect of the addition of brain-derived neurotrophic factor (BDNF) was investigated during a culture period of 5 days. Extracellular dopamine levels were measured by means of high performance liquid chromatography (HPLC) with electrochemical detection (LCEC). Our results indicate that the ratio of dopaminergic to GABAergic neurons changed in favour of the dopaminergic component when a more selective dissection technique was used. Although addition of BDNF to the cultures appeared to exert trophic influences on all the cellular components of pig fetal VM, this effect was most pronounced on the TH-positive cells. Highest extracellular DA levels were found in the VM culture with the addition of BDNF and when a more selective dissection method was used. Our in vitro findings suggest that porcine fetal dopaminergic cells retain their potential for development and outgrowth after proper explantation and dissociation. Anticipating on the results of ongoing transplantation studies in rat, they suggest that pig fetal VM can be a suitable alternative for the use of fetal human VM as a graft for Parkinson's disease.

A spinal cord ependymoma with syringomyelia is presented. The pathogenesis of syrinx formation, associated with intramedullary tumors is not fully understood. In order to examine the mechanism of formation of the tumor-associated syrinx, syrinx fluid was obtained during surgery and concentrations of proteins were measured in the syrinx fluid, the cerebrospinal fluid (CSF) and blood serum. Protein analysis of fluid specimens showed the fluid in tumor-associated syrinx to be an exudate. This strongly indicates that, in this case, intramedullary tumor-associated syringomyelia is based on disruption of the blood-brain barrier.

Assessment of estrogen receptors and progesterone receptors (PR) with PET may allow the determination of the hormone responsiveness of tumors without the need for multiple biopsies, and the monitoring of the effect of hormonal therapy. In spite of the favourable characteristics of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone ([18F]FENP) found in preclinical studies, the compound failed to reveal the presence of PR in breast carcinomas and meningiomas. In view of the clinical significance of the PR assay in human breast cancer, it is worthwhile to explore mechanisms that are potentially involved in the inadequacy of [18F]FENP to image PR with PET. Our present study on the in vivo metabolism of [18F]FENP in humans demonstrates a rapid clearance and biotransformation of the compound. Results of incubation experiments suggest that the metabolic conversion of [18F]FENP is not restricted to the liver, but also occurs in blood cells (presumably the erythrocytes) and tumors (breast carcinomas and meningiomas). The predominant metabolite of [18F]FENP in plasma during the rapid distribution phase and in tumors is identified as 20-dihydro-[18F]FENP. The conversion of [18F]FENP to its 20 alpha- or 20 beta-hydroxy metabolite has a deleterious effect on the binding affinity for PR. Our findings do not justify a conclusion as to the extent of in vivo extrahepatic biotransformation of [18F]FENP, or its significance in the ineffectiveness of [18F]FENP as an imaging agent for PR. On the other hand, the ability of breast carcinomas and meningiomas to metabolize [18F]FENP avidly appears to preclude selective imaging of PR in these tumors during the time of a PET examination. It is imperative to evaluate the metabolic stability of a [18F]fluorine labeled progestin in an early stage of future screening procedures.