Radiosurgery and whole brain therapy in the treatment of brainstem metastases

PURPOSE: The incidence of brainstem metastasis (BSM) accounts for 1-3% of brain metastases (BM). They are often associated with multiple BM and produce significant neurological symptoms. We retrospectively analyse the results of treatment with stereotactic radiosurgery (SRS). METHODS AND MATERIAL: We included the medical records of 28 patients aged 52.86+/-11.29 years; 17 (60.7%) were women. The most frequent primary tumours were breast (n=11), lung (n=9) and melanoma (n=4). A total of 30 BSM were treated with radiosurgery (SRS) with a linear accelerator (Linac Scalpel, University of Florida). The 3D planning was with image fusion. RESULTS: The mean time from the diagnosis of the primary tumour to the BM was 3+/-3.35 years; 5 cases were diagnosed simultaneously. Twenty-seven patients (96.4%) received whole brain radiotherapy, 19 before SRS and 8 after. The most usual dose was 30 Gy. Three patients underwent another SRS for other BM. The medium volume of BSM was 1.86+/-2.31 cc. The mean prescribed dose was 1114.33+/-315.6 cGy. The tumour volume did not change significantly with SRS but there was neurological improvement in 13 patients (41.9%). Twenty-four patients (85.7%) died, 22 (78.5%) due to the primary tumour: 12 cases (42.8%) due to progression of BM, 1 case due to progression of BSM and 10 due to local tumour progression or extra-cerebral metastases. Mean survival from diagnosis of BM was 22.8+/-32.4 months and from SRS of BSM, 16.8+/-31.56 months (1 month to 13.54 years). CONCLUSION: The combined treatment of SRS and whole brain radiotherapy treatment is effective in the control of BSM (only one patient died due to progression of BSM), improving the neurological symptoms in 41.9% of patients; therefore an early diagnosis and treatment is important. Many patients die due to causes other than the BSM (AU)

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Intraoperative radiation therapy in malignant glioma: early clinical results.

Intraoperative radiation therapy (IORT) with high energy electron beams is a treatment modality that has been included in multimodal programs in oncology to improve local tumor control. From August 1991 to December 1993, 17 patients with primary (8) or recurrent (9) high grade malignant gliomas, anaplastic astrocytoma (4), anaplastic oligodendroglioma (6) and glioblastoma multiforme (7), underwent surgical resection and a single dose of 10-20 Gy intraoperative radiation therapy was delivered in tumor bed. Fourteen patients received either pre-operative (8) or post-operative (6) external beam radiation therapy. Primary gliomas: 18-months actuarial survival rate has been 56% (range: 1-21+ months) and the median survival time has not yet been achieved. Four patients developed tumor progression (median time to tumor progression: 9 months). Recurrent gliomas: 18-months actuarial survival rate and median survival time has been 47% and 13 months (range: 6-32+ months) respectively. The median time to tumor progression was 11 months. No IORT related mortality has been observed. IORT is an attractive, tolerable and feasible treatment modality as antitumoral intensification procedure in high grade malignant gliomas.

Stereotactic radiosurgery of the foramen magnum region and upper neck lesions: technique modification.

A modification of the stereotactic radiosurgical procedure to permit treatment of lesions in the foramen magnum and upper cervical regions is described. The modification consists of placing the frontal pins of the stereotactic head ring in the zigoma bone, with no changes in the position of the occipital pins, so the final BRW head ring is oblique to the orbito-meatal plane. In this new position there is room enough in the posterior part of the guide for the support scrubs. This is unhampered by the patient's shoulders and the lesion is far enough to permit setting the axial coordinate sufficiently above the head ring plane.

Interaction of platelets with subendothelium in rats treated with PCA-4230, a new antithrombotic agent. Effect of PCA-4230 on experimental thrombosis.

The effects of a new antithrombotic compound, PCA-4230, versus ticlopidine were investigated using an experimental thrombosis and vascular endothelial injury model in rats. Both PCA-4230 and ticlopidine protected rat arteries from the formation of prominent thrombi and most of microthrombi without modifying the formation of a first platelet monolayer. Neither coagulation parameters nor fibrinolysis were modified by these antithrombotic drugs. Neither PCA-4230 nor ticlopidine affected thromboxane A2 production in rats, whereas unlike PCA-4230, ticlopidine inhibited ex vivo fibrinogen binding to the fibrinogen receptor found on the platelet membrane. In conclusion, PCA-4230 and ticlopidine inhibited thrombus formation in vivo by a platelet-dependent mechanism which may be different for one or the other drug in spite of the fact that the protective effect measured in this thrombosis model is quite similar for either PCA-4230 or ticlopidine. The above-mentioned results clearly show that PCA-4230 is a new potent agent with both antivascular-damaging and antiplatelet activities, and devoid of effects on coagulation and fibrinolytic systems.

Freeze-fracture cytochemistry of cholesterol content in neuronal plasma membrane following cerebral ischaemia.

Minor changes on the neuronal perikaryon cytoplasm and large alterations in neuronal processes have been demonstrated with transmission electron microscopy after 60 minutes of focal and selective cerebral ischaemia. The distribution of cholesterol in neuronal plasma membrane and perikarya plasmalemma of normal and ischaemic caudate nucleus was investigated with the polyene antibiotic filipin, a morphological probe for membrane cholesterol domains in freeze-fracture replicas. After filipin incubation of prefixed vibratome slices, filipin-cholesterol complexes appeared as 20-30 proturberances and pits on P- and E-faces. Distinct patterns of filipin-cholesterol complexes were found in non-ischaemic and ischaemic neuronal membrane. The filipin-treated specimens showed a 35-40% drop in cholesterol content in the neuronal plasmalemma one hour after cerebral ischaemia.

Intramembranous cytochemistry: a new morphological technique for studying cholesterol in the astrocyte plasma membrane of ischemic brain cells.

The distribution of cholesterol in the astrocytic plasma membranes of normal and ischemic caudate nucleus in the cat was investigated with the polyene antibiotic, filipin, a morphological probe for membrane cholesterol domains in freeze-fracture tissue replicas. After filipin incubation of prefixed vibratome slices, filipin-cholesterol complexes appeared as 20 to 30 nm protuberances and pits on P- and E-faces of the replicas. Distinct patterns of filipin-cholesterol complexes were found on nonischemic and ischemic astrocyte membranes. The filipin-treated specimens showed an 80% decrease in astroglial plasmalemma of cholesterol 1 hour after cerebral ischemia.

Adrenergic innervation of human middle cerebral artery. Ultrastructural observations.

The innervation of the human middle cerebral artery is studied with transmission electron microscopy using the chromaffin reaction technique. Adrenergic nerve fibers and related terminals, with granular electrodense neurotransmitter vesicles, are confined to the tunica adventitia-tunica media transitional zone and the outer layers of the media. These findings may indicate the presence of an adrenergic vasoconstrictor system for circulation control in the human middle cerebral artery.

Intraluminal thrombus and neointimal hyperplasia after microvascular surgery.

Despite advances in instrumentation, suture materials, and techniques, thrombosis and intimal hyperplasia due to myointimal cell proliferation are still problems in microvascular anastomosis. Platelet factors stimulate smooth-muscle cell proliferation and migration, but little is known about platelet-vessel wall interaction in microvascular surgery. This study evaluates the effect of the disposition of platelet or luminal thrombus, or both, in intimal evolution in autologous venous micrografts interposed in the common carotid artery of 30 rats. Three hours postoperatively, venous graft and suture line endothelium was completely denuded, and the host artery exhibited focal de-endothelialization. Thrombus deposition was observed on suture line and venous graft luminal surfaces, whereas host artery-denuded areas exhibited platelet adhesion. Two weeks postoperatively, intimal thickenings developed in venous graft and suture line, becoming narrower toward the venous graft. The distribution and size of intimal thickening did not change significantly at later observation periods (3-8 months). Intimal thrombus deposition and intimal hyperplasia, appearing in later stages of evolution, show a similar pattern of distribution.

Quantitative electron microscopic study of calcium accumulation in cerebral ischemia mitochondria.

Formation of calcium deposits in mitochondria is a consistent feature of irreversible injury in ischemic myocardium. We studied calcium accumulation in nerve cell mitochondria in a cat model 30 and 60 minutes after cerebral ischemia localized in the anterior part of the caudate nucleus and adjacent internal capsule. In control animals, calcium deposits were visible in synaptic vesicles, Golgi apparatus, mitochondria, lysosomes, and in glial and neuronal nuclei. After cerebral ischemia, findings included astrocytic swelling and degeneration of neurons, with an increase in calcium pyroantimoniate mitochondrial deposits. Content of intramitochondrial calcium deposits is related to duration of ischemia as well as the amount of cellular lesions.

Absence of filipin-sterol complexes from the ciliary necklace of ependymal cells.

The polyene antibiotic filipin reacts specifically with membrane cholesterol and produces membrane perturbations. Prefixed vibratome slices of cat ependymal cells were treated with a glutaraldehyde solution containing 300 microM filipin. Freeze-fracture of these cells revealed numerous 25-30 nm protuberances on fracture faces (filipin-sterol complexes) in the ciliary membrane. In the ciliary necklace, however, these filipin-sterol complexes were absent. These results suggest that the ciliary necklace has a low cholesterol content.

Possible role of endothelium in the orientation of smooth muscle cells in experimental neointima.

Myointimal cells (MIC) orientation and intimal thickening evolution, induced by grafting an autogenous venous patch onto the rat common carotid artery, were studied with light microscopy at different times until 14 months after surgery. Intimal thickenings in the venous patch were most prominent at an intermediate postoperative period, after which their mean size did not change significantly. In host artery neointima, the greatest MIC proliferation was observed at a late stage of evolution. MIC arrangement was predominantly circumferential to the blood stream in venous patch neointima, whereas it was mostly axial in the host artery. The interaction between MIC orientation and endothelial regeneration in the operated vessel is discussed.

Disturbance of plasmalemmal astrocytic assemblies in focal and selective cerebral ischemia.

Selective cerebral ischemia was induced in the caudate nucleus of seven normothermic anesthetized cats through transorbital clamping of the anterolateral penetrating lenticulostriated arteries. The plasmalemma of astrocytic foot processes has been studied with the freeze-fracture technique and conventional electron microscopy 10, 15 and 30 min after ischemia. After 15 min of circulatory arrest, assemblies of intramembrane particles (IMPs) disappear in some areas of astroglial perivascular plasmalemma in the ischemic caudate nucleus. Interastrocytic gap junctions do not change significantly. 30 min after ischemia, the pericapillary astroglial end foot is expanded and organelles are greatly perturbed (cytotoxic edema). Although the function of astrocytic intramembrane particle assemblies is unclear, it is postulated that the disappearance of this membrane specialization may play a role in the pathophysiology of cytotoxic astroglial edema.

Aspects of interastrocytic gap junctions in blood-brain barrier in the experimental penumbra area, revealed by transmission electron microscopy and freeze-fracture.

Interastrocytic gap junctions in the blood-brain barrier of the experimental penumbra area were studied in the cat caudate nucleus 1 h after ischemia. Transmission electron microscopy and freeze-fracture studies revealed only slight changes in gap junctions between astrocytes, indicating that these junctions are very resistant to hypoxia.

Assemblies of intramembranous particles in astrocytoma: a preliminary report.

A human astrocytoma has been studied with the freeze-fracture technique. The astrocytic membrane presents many assemblies formed by aggregations of intramembranous particles (5.8-7.8 nm in diameter) in P-face arranged in a square, and complementary pit assemblies in E-face. In the interastrocytic gap junctions the connexions are packed in a crystalline array.

Pericyte endothelial gap junctions in human cerebral capillaries.

Human cerebral tissue has been ultrastructurally studied and gap junctions have been visualized between endothelial cells and pericytes that permit ion exchange. We propose that the functional interrelationship between endothelium and pericytes may play a role in the alteration of capillary diameter for the control of local cerebral blood flow.

Are the pores of intramembrane particles of postsynaptic membrane transmitter-dependent channels?

The rat neonatal cerebellar cortex has been studied using the freeze fracture technique. In the dendritic postsynaptic membrane, intramembrane particles containing an electron-dense central area have been detected. This type of area could be a platinum aggregate within a channel which, crossing the particle, may connect the postsynaptic cytoplasm with the synaptic cleft.

Specific endothelial granules in venous patch neoendothelium in the rat.

Weibel-Palade bodies were observed in the neoendothelium and capillaries of vasa vasorum of autologous 'venous patches' grafted in the common carotid artery of the rat. These corpuscles varied in number and distribution but were most frequently found in the luminal area of endothelial cytoplasm. In venous patch neoendothelium, the shape, size and substructure of Weibel-Palade bodies were similar to those in other types of vascular endothelium. These specific endothelial granules were more numerous during the week following neoendothelium formation. It is proposed that these corpuscles may play a role in the proliferation of endothelial cells in venous patches.

Smooth muscle cells in 'venous patches'grafted into the rat common carotid artery. A structural study.

In the 2nd week after surgery, well differentiated smooth muscle cells (SMC) were evident in the walls of venous patches in rat common carotid artery. Gap junctions were the only type of intercellular junction observed between SMC in the present study.