The changes of cerebral blood flow and metabolism of normal brain tissue after surgery, radiation, and chemotherapy in brain tumor patients: evaluated by position emission tomography

The changes of cerebral blood flow (CBF) and metabolism of normal brain tissue after surgery, radiation, and chemotherapy in brain tumor patients were measured by positron emission tomography (PET). The subjects consisted of 6 men and 3 women, and were from 11 to 62 years old. Those were four patients with glioblastomas, one patient with malignant oligodendroglioma, one patient with astrocytoma grade II, one patient with astrocytoma grade III, one patient with pontine glioma, one patient with pineal germinoma. Seven patients were operated and pathohistologically diagnosed. Two patients with pineal germinoma and pontine glioma were not operated and radiologically diagnosed. Of 7 operated patients, first PET was performed before operation in 3 patients, and from 10 to 16 days after operation in 4 patients. Following first PET, the patients were treated with irradiation (1 case), or with both irradiation and chemotherapy (8 cases). The total radiation dose for tumor was from 59 to 61 Gy distributed in a period of 6-8 weeks. Whole brain irradiation was performed up to 30 or 40 Gy, with a remaining dosimetry (20-30 Gy focused on the tumor field. Chemotherapy consisted of intravenous administration of ACNU and oral administration of FT-207. Second PET was performed 1 month after therapy (9 cases), and third PET was performed from 4 to 24 months after therapy (6 cases). Fourth PET was performed in 2 patients (22 and 35 months after therapy), and fifth PET was performed in one patient (35 months after therapy).(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on DNA fragmentation and disruption of the blood-brain barrier in delayed radiation injuries in the rat brain

Delayed effect of radiation injury to the central nervous system often results in improper prognosis for the patients with malignant brain tumors. Two types of cell, the endothelial cell and the oligodendrocyte, are considered to be causative lesions for delayed radiation injury. Recently, morphological studies with both light and electron microscope have also indicated involvement of apoptosis at the acute stage of radiation injury. In the rat radiation injury model, we first examined the capillary endothelial cells when they were damaged after irradiation, using immunohistochemical analysis of endothelial blood antigen (EBA) as one of the indicators of normal function of the blood-brain barrier (BBB). Secondly, we examined the types and location of DNA-fragmented cells using in situ end-labeling using the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling) method. A single dose of 10, 20 or 30 Gy was irradiated to the hemispheres and the brains were analyzed at 3, 6 and 12 months later. Although damage of endothelial cells was seen in the brains at 6 months after 20 Gy irradiation, disruption of BBB, as indicated by no immunoreactivity of EBA, occurred only in the brains at 12 months after 30 Gy irradiation. DNA fragmentation, indicated by TUNEL positive cells, were shown in the oligodendrocyte, astrocytes and endothelial cells in the brains at 6 months after 20 Gy irradiation. The results suggest that both disruption of BBB and apoptosis in the glial cells and endothelial cells are involved in the delayed radiation injury in the rat brain.     

大鼠半脑照射后海马细胞外液谷氨酸含量的变化

目的 :探讨早期放射性脑损伤的机制。方法 :用在体微透析结合高效液相色谱法 ,对大鼠半脑照射后测定海马细胞外液谷氨酸含量。结果 :发现半脑照射后半个月照射侧谷氨酸含量上升 ,并与剂量相关 ,15Gy组和 3 0Gy组与未照射侧相比有显著差异。照射后 3个月恢复正常。结论 :认为谷氨酸神经递质的变化可能是放射性脑损伤综合作用的结果。     

Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia

Brain tumor patients who are long-term survivors after whole-brain irradiation (WBI) often suffer cognitive impairment, including dementia. Although the pathogenic mechanisms remain poorly understood, our studies suggest that radiation-induced cognitive impairment may be a form of vascular dementia. We used a fractionated dose of gamma-rays that is biologically similar to that given to brain tumor patients. The brains of adult rats were irradiated with 40 Gy, in eight 5 Gy fractions over 4 weeks. Cognitive function was assessed prior to WBI and up to 9 months post-irradiation using a partially-baited radial arm maze. A significant increase in working memory errors was found in the irradiated rats by two-way ANOVA (p=0.0042). The increased errors occurred primarily at 6 and 9 months (p < 0.05, student's t-test). Vessel density was quantified using a stereology method with computerized image processing and analysis. Vessel density was unchanged 24 h after the last dose, but significantly decreased (p=0.002), by approximately 30%, from 10 weeks to 52 weeks. Thus, cognitive impairment arose after brain capillary loss in irradiated rats that show no other gross brain pathology. Capillary loss may play an important role in radiation-induced dementia and this may be a model of vascular dementia.     

伽玛刀照射猫视神经后视神经病理学变化研究

目的 探讨引起视神经病理学变化的最小射线剂量。方法 20只家猫随机分成5组，每组4只，1组作为对照组，其余4组分别接受10Gy、11Gy、12Gy、13Gy伽玛刀的照射，照射后5个月，取病理，分别进行光镜及透射电镜检查，重点观察其电镜下超微病理结构的变化。结果 10Gy组结构正常，11Gy组光镜下结构出现轻微的变化，电镜下超微病理结构出现部分线粒体肿胀。12Gy组光镜及电镜下神经组织结构紊乱，广泛变性。13Gy组神经组织结构严重紊乱，大部分髓鞘脱失、溶解，神经微丝疏松、溶解，线粒体普遍空泡化、溶解改变。结论 引起视神经病理学变化的射线剂量为11Gy，引起视神经病理学质变的最小射线剂量为12Gy，随着剂量的增加对视神经的损伤加重。     

伽玛刀照射正常脑组织引起的放射生物学变化

不同剂量伽玛刀照射猫的大脑皮层,照射后不同时期(1个月,3个月,半年,1年)分别观察其组织学变化。结果:160Gy,180Gy,200Gy伽玛刀术后1个月均引起脑组织坏死,200Gy产生的坏死灶较大;100Gy,70Gy3个月时未见组织坏死,1年时引起严重晚期反应;50Gy,40Gy引起晚期迟发放射反应;30Gy1年时仅局部细胞数量减少,20和10Gy无变化。30Gy可能是伽玛刀引起脑组织放射反应的阈剂量。     

Quantification of microglial late reaction to stereotactic irradiation of the rat brain using computer-aided image analysis

The role of microglial cells in the late delayed reaction following radiotherapy of brain tumors has not been elucidated. To investigate the late delayed response of microglial cells to radiation, we stereotactically irradiated spherical treatment volumes in the right frontal lobe of rat brains. Doses of 20, 30, 40, and 50 Gy were used in combination with two different collimators. The response of microglial cells at 10 and 19 months after irradiation was determined with Anti-CD 11 b/c (Ox 42) as an immunohistochemical marker. For evaluation of immunostaining, we developed a method using computer-aided image analysis in which the ratio of the area of stained cells to that of nonstained brain tissue is calculated. In addition, quantification of Ox-42+ cells per microscopic field was performed. Animals treated with 30 Gy or more had significantly increased total areas of staining at both time points studied. In contrast, the number of stained cells at 10 months increased significantly only in animals treated with 30 or 40 Gy. Likewise, at 19 months, this number increased significantly only in animals treated with 40 Gy or more. These results indicate that computer-aided determination of the area of stained cells is more sensitive than the counting of stained cells. We have demonstrated that microglial cells respond to stereotactic irradiation in a dose-dependent fashion. The image analysis we employed for this purpose is a systematic method to evaluate immunohistochemical staining.     

Molecular responses of brain endothelial cells to radiation in a mouse model

Although most small arteriovenous malformations (AVM) are curable, over 90% of large lesions are untreatable with current surgery or radiosurgery. Endothelial cells (EC) are believed to be pivotal in the resulting vascular changes after AVM are irradiated, although their role is not fully understood. Elucidating the molecular effects of radiation on EC may allow development of new therapies that modulate the response of AVM to radiation. Cultured murine cerebral EC (bEnd.3) were exposed to a single 25 Gy dose of ionising radiation from a linear accelerator. Expression of the membrane proinflammatory and thrombotic molecules E-selectin, tissue factor (TF) and thrombomodulin (TM) were examined by immunofluorescent staining at times up to three weeks post irradiation. We found that E-selectin is significantly down regulated in the first 24 hours after irradiation. Later there is no significant difference in expression of this molecule between irradiated and non-irradiated groups. TM expression was significantly increased at all times, and the staining intensity of TF remained unchanged three weeks post irradiation. These results contribute to a greater understanding of the proinflammatory and thrombotic changes caused by irradiating normal brain EC.     

伽玛刀治疗脑转移瘤46例临床分析

目的：伽玛刀是治疗脑转移瘤的一种途径，尤其对多发病灶者。方法：用伽玛刀治疗脑转移瘤随访１０个月以上者共４６例，其中单发２７例，多发１９例，共１０３个病灶。结果：脑转移瘤相对较小，而靶周边剂量相对较大者，完全缓解率较高。结论：无论单发及多发病灶伽玛刀治疗１年存活率均较开颅手术为高。多发病灶需配合全脑放疗及化疗，否则易产生新病灶，使病情进展。     

伽玛刀照射猴三叉神经的病理组织学研究

目的 观察伽玛刀照射猴三叉神经的病理组织学变化,探讨伽玛刀治疗原发性三叉神经痛(TN)的放射生物学效应机制和照射神经长度-剂量的效应关系.方法 选择5只恒河猴,1只为对照,4只行伽玛刀照射,选择靶点为三叉神经根,一侧为单靶点照射,对侧为双靶点照射,给予剂量分别为60 Gy、70 Gy、80 Gy、100 Gy.照射后6个月取病理,行光镜、透射电镜及免疫组织化学检查.结果 在相同剂量照射下,单靶点照射与双靶点照射的神经组织结构损伤程度变化基本一致.60 Gy、70 Gy见少许神经纤维脱髓鞘,轴突变性、断裂或消失.80 Gy神经组织结构损伤程度加重.100 Gy神经组织结构损伤程度更重,可见部分神经坏死.结论 60 Gy、70 Gy对三叉神经的组织结构变化影响小,80 Gy可引起三叉神经部分轴突的变性、消失及脱髓鞘,更高的剂量(100 Gy)可导致部分神经坏死.单靶点照射与双靶点照射神经组织结构损伤程度相近,两者的照射神经长度-剂量效应关系差异无统计学意义.     

Effects of prenatal irradiation on the development of cerebral cortex and corpus callosum of the mouse

Defects of the cerebral cortex and corpus callosum of mice subjected prenatally to gamma irradiation were evaluated as a function of dose and of embryonic age at irradiation. Pregnant mice were exposed to a gamma source at 16, 17, and 19 days of gestation (E16, E17, and E19, respectively), with total doses of 2 Gy and 3 Gy, in order to produce brain defects on their progeny. At 60 postnatal days, the brains of the offspring were analyzed qualitatively and quantitatively and compared with those of nonirradiated animals. Mice irradiated at E16 were all acallosal. Those that were exposed to 2 Gy displayed an aberrant longitudinal bundle typical of other acallosals, but this was not the case in those irradiated with 3 Gy. The corpus callosum of animals irradiated at E17 with 3 Gy was pronouncedly hypotrophic, but milder effects were observed in the other groups. Quantitative analysis confirmed a dependence of callosal midsagittal area upon dose and age at irradiation, and, in addition, indicated an interaction between these variables. The neocortex of irradiated animals was hypotrophic: layers II-III were much more affected than layer V, and this was more affected than layer VI. Quantitative analysis indicated that this effect also depended on dose and age at irradiation and that it was due to a loss of cortical neurons. Furthermore, a positive correlation was found between the number of neurons within layers II-III, and V and the midsagittal area of the corpus callosum. Ectopic neurons were found in the white matter and in layer I of animals irradiated at E16 and E17, indicating that fetal exposure to ionizing radiation interfered with the migration of cortical neuroblasts.     

伽玛刀照射正常大鼠海马组织形态学结构的变化

目的研究伽玛刀照射对正常大鼠海马组织形态学结构的影响。方法利用自行设计的伽玛刀大鼠立体定位头架，分别应用剂量为20、40、60、80、100和150Gy的伽玛射线对大鼠海马组织进行照射。采用电镜观察照射后海马神经细胞超微形态结构变化，MRI观察影像学表现。结果电镜结果显示：100Gy和150Gy剂量引起海马神经细胞严重损伤，60Gy引起轻度损伤，在40Gy时胶质细胞和血管内皮细胞已有肿胀。100Gy照射后，1个月内大鼠靶区无影像学改变，3个月时大鼠靶区表现为高信号。结论海马组织的损伤程度与伽玛刀的照射强度存在剂量一效应关系和时间一效应关系，海马神经元比胶质细胞和血管内皮细胞更具放射耐受性。     

Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice

Advances in the management of pediatric brain tumors have increased survival rates in children, but their quality of life is impaired due to cognitive deficits that arise from irradiation. The pathogenesis of these deficits remains unknown, but may involve reduced neurogenesis within the hippocampus. To determine the acute radiosensitivity of the dentate subgranular zone (SGZ), 21-day-old C57BL/J6 male mice received whole brain irradiation (2-10 Gy), and 48 h later, tissue was assessed using immunohistochemistry. Proliferating SGZ cells and their progeny, immature neurons, were decreased in a dose-dependent fashion. To determine if acute changes translated into long-term alterations in neurogenesis, mice were given a single dose of 5 Gy, and 1 or 3 months later, proliferating cells were labeled with 5-bromo-2'-deoxyuridine (BrdU). Confocal microscopy was used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes. X-rays significantly reduced the production of new neurons at both time points, while glial components showed no change or small increases. Measures of activated microglia and infiltrating, peripheral monocytes indicated that reduced neurogenesis was associated with a chronic inflammatory response. Three months after irradiation, changes in neurogenesis were associated with spatial memory retention deficits determined using the Morris water maze. Behavioral training and testing increased the numbers of immature neurons, most prominently in irradiated animals. These data provide evidence that irradiation of young animals induces a long-term impairment of SGZ neurogenesis that is associated with hippocampal-dependent memory deficits.     

Effect of neutron-gamma radiation on dopamine and serotonin metabolism in the rat brain: a regional analysis

The concentrations of dopamine (DA) and its metabolites and the levels of 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of serotonin, were determined in discrete cerebral areas of rats 3 hr after (neutron-gamma) irradiation at 4 and 7 Gy. After the 7 Gy irradiation, no significant effect was observed. After the 4 Gy exposure, the most marked difference between irradiated and control rats was in the levels of DA and its metabolites in the striatum. We observed a decrease of DA, HVA, and DOPAC levels in the striatum and an opposite pattern in the substantia nigra. Whatever the brain area observed, an increase of 5-HIAA levels was noted.     

Neurobiological responses to stereotactic focal irradiation of the adult rodent hippocampus

Radiation effectively treats brain tumors and other pathologies but dose and treatment plans are limited by normal tissue injury, a major cause of morbidity in survivors. Clinically significant normal tissue injury can occur even with therapies that target pathological tissue and limit out-of-target irradiation. Elucidating the mechanisms underlying normal tissue injury is facilitated by studying the effects of focal irradiation and comparing irradiated and un-irradiated tissue in experimental animals. Young adult rats were irradiated using the Leksell Gamma Knife? with a 10 Gy maximum dose directed at the left hippocampus and shaped to minimize irradiation contralaterally. At least 95% of targeted hippocampus received ≥3 Gy, while all points in the contralateral hippocampus received <0.3 Gy. Neuronal and microglial markers of damage were assessed in the targeted and contralateral hemispheres of Gamma Knife?-treated rats and compared to non-irradiated controls. Acute cell death and sustained changes in neurogenesis and in microglia occurred in the dentate gyrus of the targeted, but not the contralateral, hippocampus, providing experimental evidence that focal irradiation at doses received by peri-target regions during targeted radiation therapy produces robust normal tissue responses. Additional studies using this approach will facilitate assessment of in vivo dose responses and the cellular and molecular mechanisms of radiation-induced brain injury.     

Delayed brain hemorrhage associated with prophylactic whole brain irradiation for pediatric malignant brain tumor: a case report

Intraparenchymal hemorrhage in the left frontal lobe suddenly occurred in a 7-year-old girl who had undergone partial removal of an undifferentiated brain stem glioma and received craniospinal (30 Gy) and posterior fossa booster (20 Gy) irradiation at the age of 20 months. The brain hemorrhage was thought to be delayed irradiation effect. Follow-up neuro-imaging at age 9 years showed two more small occult chronic and subacute hemorrhages in the brain. The possibility of repeated hemorrhage as a delayed reaction to brain irradiation is emphasized.     

Effects of gamma radiation on the shark brain

Summary A comparison was made between the effects of gamma radiation on the elasmobranch and the mammalian brain. Thirty-seven nurse sharks (ginglymostoma cirratum) received a single exposure, in a range of 1 000 to 30 000 rads, to the brain. The animals remained seemingly unaffected in their behavior and at their sacrifice, between one day and 28 months after irradiation, no histological changes could be detected with the exception of one shark (exposed to 30 000 and sacrificed after 12 months) which showed two small necrotic lesions in the tegmentum. No detectable difference in amount and distribution of glycogen in the brain could be demonstrated between irradiated and non-irradiated sharks. Also, the irradiated sharks showed no changes of the blood-brain barrier to protein tracer.Rats irradiated with 25 000 to 30 000 rads to the brain from the same source died shortly after exposure or showed extensive necrotic lesions in the brain. These was also an intense accumulation of glycogen mostly in the astrocytes and a widespread disturbance of the bloodbrain barrier to Evans Blue-albumin tracer.     

Carbon monoxide poisoning-induced nigrostriatal dopaminergic dysfunction detected using positron emission tomography (PET)

A malfunctioning heater caused a severe carbon monoxide (CO) intoxication leading to unconsciousness and predominantly right-sided extrapyramidal syndrome in a 29-year-old man. Follow-up included thorough clinical monitoring, and brain MRI and PET studies. Nine days after the poisoning, brain MRI showed symmetrical necrosis in the globus pallidi, but no abnormality was found in the substantia nigra. In addition, white matter periventricular lesions were seen. In a control scan 14 months later the white matter changes had subsided but small necrotic lesions were still noted bilaterally in the globus pallidi. A 6-[¹⁸F]fluoro-l-dopa PET examination performed 5 weeks after the intoxication revealed impaired presynaptic dopaminergic function in the left putamen whereas in the right putamen the dopaminergic activity was within normal limits. [¹¹C] raclopride PET imaging 4 months after the poisoning showed no abnormality in postsynaptic D2 binding in the striatum. Clinically, the parkinsonian symptoms resolved 1.5 years after the poisoning. The final outcome of the recovery was excellent, and the patient returned to work. This is the first case reported where unilateral presynaptic, dopaminergic hypofunction in putamen could be confirmed with fluoro-l-dopa PET imaging on a patient with extrapyramidal syndrome caused by CO poisoning. Our results emphasize that CO intoxication can lead to striatal dopaminergic hypofunction, and that PET is a sensitive tool in evaluating extrapyramidal system after sudden neurotoxic insult.     

The first experience in interstitial brachytherapy for primary and metastatic tumors of the brain

In 2001-2002, the authors performed a course of brachytherapy in 15 patients with inoperable primary, recurrent, and metastatic brain tumors. The histostructural distribution was as follows: low-grade astrocytoma (grade II according to the WHO classification) in 2 patients, anaplastic astrocytoma (AA) in 3, glioblastoma multiforme (GBM) in 5. Five patients had solid tumor deposits in the brain. Computer tomographic (CT) and magnetic resonance imaging (MRI) data were used to define a path for forthcoming biopsy and implantation at a "Stryker" navigation station, by taking into account the anatomy of the brain, vessels, and functionally significant areas. After having histological findings, plastic intrastats whose number had been determined by the volume of a target were implanted into a tumor by the predetermined path. Dosimetric planning was accomplished by using CT and MRI images on an "Abacus" system. The final stage involved irradiation on a "GammaMed plus" with a source of 192Ir. Irradiation was given, by hyperfractionating its dose (3-4 Gy twice daily at an interval of 4-5 hours) to the total focal dose (TFD) of 36-44 Gy. Patients with gliomas untreated with radiation also underwent external radiation in a TFD of 54-56 Gy and patients with brain metastases received total external irradiation of the brain in a TFD of 36-40 Gy. The tolerance of a course of irradiation was fair. In patients with AA and GBM, one-year survival was observed in 66 and 60%, respectively; in those having metastasis, it was in 20%. Six patients died from progressive disease. All patients with low-grade astrocytoma and one patient with anaplastic astrocytoma were alive at month 24 after treatment termination. The mean lifespan of patients with malignant gliomas and solid tumor metastasis was 11.5 and 5.8 months, respectively. Brachytherapy is a noninvasive and tolerable mode of radiotherapy that increases survival in some groups of patients with inoperable brain tumors.     

Stereotactic radiotherapy for cerebral metastases using CyberKnife

During recent decade development of frameless techniques of fixation enabled introduction of stereotactic radiation therapy in metastatic brain lesions and made possible irradiation of large foci involving or proximal to eloquent and critical brain areas. This paper focuses on comparative analysis of effectiveness of hypofractionation (HRST) and radiosurgery (SRS) using CyberKnife system in cerebral metastases. Since November 2009 till June 2011 54 patients with cerebral metastases were treated using CyberKnife system. Age of patients ranged between 25 and 77 years (mean 54 years). 16 patients received radiosurgical treatment (mean total dose was 22.5-35 Gy, number of fractions varied from 2 to 7, mean volume of irradiation was 22.69 cm3) and 8 patients were treated by HRST with RS of selected foci (mean total dose reached 23 and 30 Gy, mean volume of irradiation was 1.02 cm3 and 11.19 cm3, respectively). Indices of overall regression and stabilization of disease for HRST and SRS groups were 81% and 79%, respectively. With mean follow-up period of 12.3 (1-16.1) months median survival for SRS and HRST reached 6.38 (1-15.8) and 6.2 (0.2-16.1) months and median recurrence-free survival was 3.6 (1-13.6) and 5.5 (2-14.2) months, respectively. Obtained results confirmed biological advantages of fractionated stereotactic radiotherapy of large cerebral tumors in comparison with radiosurgery. Prospective studies with rigid criteria of inclusion are required to determine optimal dose/volume/fractionation interrelations in stereotactic radiation treatment of cerebral metastases.