脑脊液肿瘤标志物检查在脑膜转移瘤诊断中的价值

目的:通过分析脑膜转移瘤的临床特点、增强MRI表现、脑脊液肿瘤标志物检查结果，提高对脑膜转移瘤的认识程度，并寻找有效的检查方法。方法:回顾分析我院肿瘤内科2011年10月至2017年6月收治的23例脑膜转移瘤患者，从临床表现、脑膜增强MRI表现、脑脊液肿瘤标志物检测以及与血清肿瘤标志物进行对比的结果进行统计分析。结果:23例患者中脑脊液肿瘤标志物、细胞学和影像学阳性表达率分别为82.61%、56.52%和65.22%；以单一标志物CEA为独立观察指标，当脑脊液中CEA含量高表达时，脑脊液细胞学、脑膜强化MRI的阳性检出率也增加；当脑脊液肿瘤标志物多种阳性表达时，脑脊液细胞学、脑膜强化MRI阳性率也增加，三者之间密切相关，具有统计学意义（P＜0.05）。肿瘤标志物在脑脊液中的阳性表达与在血清中呈对应关系。结论:脑脊液细胞学检查和增强MRI是脑膜转移瘤的主要诊断依据，脑脊液肿瘤标志物联合脑膜增强MRI弥补了细胞学检查的缺陷，提高诊断准确率。     

Prognostic value of cerebrospinal fluid cytology in pediatric medulloblastoma

Background: Although the demonstration of leptomeningeal dissemination is the most important predictor of poor outcome in children with medulloblastoma, there is lack of consensus on the prognostic value of a positive cerebrospinal fluid (CSF) cytology (i.e., stage M1).Patients and methods: Eighty-six pediatric medulloblastoma patients treated in Switzerland between 1972–1991 were retrospectively studied regarding the influence of M-stage on prognosis. 39 were M0, 13 M1, 15 Mx, 17 M2, and 2 M3.Results: Five- and 10-year overall survival rates were 76% and 54% for M0, 68% and 50% for Mx, 36% and 25% for M1, and 22% and 22% for M2–3 (P < 0.001), respectively. No significant survival differences were observed between M1 and M2–3 patients. Among 26 patients with only postoperative CSF cytologies, seven were positive. Their outcome was similar to that of six preoperatively staged M1 and significantly different from that of M0 patients (P = 0.001). In 14 patients both pre- and postoperative CSF cytology was performed. Total agreement was observed between the pre- and postoperative results (six positive and eight negative). Among the 19 M2–3 patients CSF cytology was positive in eight, negative in five, and unknown in six.Conclusions: A positive CSF cytology either pre- or postoperatively predicts for a poor outcome, similar to that observed in stage M2–3 patients. A postoperative cytology is likely to be concordant with cytologic results obtained preoperatively, and seems to have the same prognostic significance. A negative cytology, however, does not exclude a more advanced stage.     

Biochemical evidence for viral-like characteristics in cerebrospinal fluids of brain tumor patients.

Previous work done in this laboratory has shown that human Central Nervous System tumors possess attributes in common with those found in RNA tumor viruses. Because of the intimate physical relationship between the circulating cerebro-spinal fluid and the Central Nervous System, particles derived from tumors in this system may very well be shedded into the surrounding fluid system thus displaying similar biochemical attributes. Twenty samples of cerebro-spinal fluids were examined. Fifteen were from patients with various types of tumors in various location of the Central Nervous System. Five were from patients with unrelated diseases. Eleven or 74% of those from tumor patients were found to be positive when simultaneous detection assays were done on their core structures. None of the control was positive. The [3H]DNA synthesized from core structures hybridized readily to polysomal RNAs from a solid tumor. Particles from them were found to have a density of 1.867 g/ml sucrose gradient.     

Various components of the insulin-like growth factor system in tumor tissue, cerebrospinal fluid and peripheral blood of pediatric medulloblastoma and ependymoma patients

The insulin-like growth factor (IGF) system plays an important role in neuronal development and may contribute to the development of brain tumors. In this study, we studied mRNA expression levels of IGFs, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor receptors (IGFRs) in 27 pediatric medulloblastomas, 13 pediatric ependymomas and 5 control cerebella. Compared to normal cerebellum, mRNA levels of IGFBP-2 and IGFBP-3 were significantly increased in medulloblastomas and ependymomas. IGFBP-2 expression was indicative of poor prognosis in medulloblastomas, whereas IGFBP-3 mRNA levels were especially high in anaplastic ependymomas. IGFBP-5 and IGF-II mRNA levels were significantly increased in ependymomas compared to control cerebellum. Protein expression levels of IGFs and IGFBPs were analyzed in the cerebrospinal fluid (CSF) of 16 medulloblastoma, 4 ependymoma and 23 control patients by radioimmuno assay to determine whether they could be used as markers for residual disease after surgery. No aberrant CSF protein expression levels were found for ependymoma patients. In medulloblastoma patients, the IGFBP-3 protein levels were significantly higher than in ependymoma patients and controls. Moreover, enhanced levels of proteolytic fragments of IGFBP-3 were found in the CSF of medulloblastoma patients, being in concordance with a significantly increased IGFBP-3 proteolytic activity in the CSF of these patients. In conclusion, our data suggest that the IGF system is of importance in pediatric medulloblastomas and ependymomas. Larger studies should be conducted to validate the predictive values of the levels of intact IGFBP-3 and proteolytic fragments in CSF in the follow-up of medulloblastomas.     

Developmental model relating white matter volume to neurocognitive deficits in pediatric brain tumor survivors

BACKGROUND: The primary objective of this study was to test the hypothesis that, among survivors of pediatric brain tumors, the association between reduced volumes of normal-appearing white matter (NAWM) and intellectual/academic achievement deficits can be explained by patient problems with memory and attention. METHODS: Quantitative tissue volumes from magnetic resonance imaging scans and neurocognitive assessments were obtained for 40 long-term survivors of pediatric brain tumors. They were treated with radiotherapy (RT) with or without chemotherapy 2.6-15.3 years earlier (median, 5.7 years) at an age of 1.7-14.8 years (median, 6.5 years). Neurocognitive assessments included standardized tests of intellect (intelligence quotient [IQ]), attention, memory, and academic achievement. RESULTS: Analyses revealed significant impairments in patients' neurocognitive test performance on all measures. After statistically controlling for age at RT and time from RT, significant associations were found between NAWM volumes and both attentional abilities and IQ, and between attentional abilities and IQ. Subsequent analyses supported the hypothesis that attentional abilities, but not memory, could explain a significant amount of the relationship between NAWM and IQ. The final developmental model predicting academic achievement based on NAWM, attentional abilities, and IQ explained approximately 60% of the variance in reading and spelling and almost 80% of the variance in math. CONCLUSIONS: The authors demonstrated that the primary consequence of reduced NAWM among pediatric patients treated for brain tumors was decreased attentional abilities, leading to declining IQ and academic achievement.     

Evaluation of tumor marker S-100 in cerebrospinal fluid from subjects with nonischemic brain pathologies.

In order to evaluate the S-100 concentration in cerebrospinal fluid from subjects with nonischemic brain damage, a total of 33 samples were analyzed: 11 from subjects in whom no organic disease could be found; 14 from patients with a diagnosis of lymphocytic or bacterial-fungal meningitis, and 8 from patients with acute lymphatic leukemia but no demonstrable signs of meningeal involvement. In all cases, the subjects considered had no previous history of melanoma or ischemic brain damage. The mean levels +/- SEM found for each study group were 1.00 +/- 0.11, 1.67 +/- 0.23 and 1.17 +/- 0.14 microg/l, respectively. Significant differences appeared between the groups when applying the Kruskal-Wallis nonparametric test (p = 0.035). The highest levels were found in the meningitis group and were significantly different from those of the control group (p = 0.015). No significant differences were found with regard to age or sex. Based on the pathophysiology of meningitis and on previous studies, the results suggest the existence of brain damage caused by an infection as a possible cause of increased S-100 levels.     

Blood–brain barrier and blood–cerebrospinal fluid barrier in normal and pathological conditions

Blood-borne substances can invade into the extracellular spaces of the brain via endothelial cells in sites without the blood–brain barrier (BBB), and can travel through the interstitial fluid (ISF) of the brain parenchyma adjacent to non-BBB sites. It has been shown that cerebrospinal fluid (CSF) drains directly into the blood via the arachnoid villi and also into lymph nodes via the subarachnoid spaces of the brain, while ISF drains into the cervical lymph nodes through perivascular drainage pathways. In addition, the glymphatic pathway of fluids, characterized by para-arterial pathways, aquaporin4-dependent passage through astroglial cytoplasm, interstitial spaces, and paravenous routes, has been established. Meningeal lymphatic vessels along the superior sagittal sinus were very recently discovered. It is known that, in mice, blood-borne substances can be transferred to areas with intact BBB function, such as the medial regions of the hippocampus, presumably through leaky vessels in non-BBB sites. In the present paper, we review the clearance mechanisms of interstitial substances, such as amyloid-β peptides, as well as summarize models of BBB deterioration in response to different types of insults, including acute ischemia followed by reperfusion, hypertension, and chronic hypoperfusion. Lastly, we discuss the relationship between perivascular clearance and brain disorders.     

Penetration of 3-deazauridine into human brain, intracerebral tumor, and cerebrospinal fluid.

The antitumor agent 3-deazauridine (DAU) was administered rapidly to four patients before surgical removal of intracerebral tumor. Tumor, adjacent brain tissue, and temporalis muscle were assayed for DAU by high-pressure liquid chromatography. DAU penetrated comparably into tumor, brain, and muscle; in one patient, tissue concentrations were higher than concurrent plasma concentrations. The active metabolite 3-deazauridine 5'-triphosphate was quantitated in one tumor sample and greatly exceeded its Ki for cytidine 5'-triphosphate synthetase. DAU was also present in autopsy brain specimens from two patients treated shortly antemortem. Cerebrospinal fluid concentrations were 22.1 and 59.0%, respectively, of concurrent plasma concentrations during continuous infusion of DAU in two patients. Cerebrospinal fluid concentration was 3.1 microgram/ml 2 hr after a 30-min infusion of 1.5 g of drug per sq m and fell to 1.9 microgram/ml at 16 hr. Thus, DAU is capable of penetrating into intracerebral tumor, brain, and cerebrospinal fluid and is worthy of investigation in the treatment of intracerebral and meningeal neoplasms.     

Fronto-limbic white matter microstructure,behavior, and emotion regulation in survivors of pediatric brain tumor

Journal of Neuro-Oncology - After treatment, pediatric brain tumor survivors (PBTS) face emotional and behavioral challenges, perhaps due to tumor or treatment-related changes in brain structures...     

The role of monoclonal antibodies in brain tumour diagnosis and cerebrospinal fluid (CSF) cytology

Summary This paper reviews the diagnostic role of monoclonal antibody immunohistochemistry in a series of 189 brain tumour biopsies and 22 cases of neoplastic meningitis. The diagnostic monoclonal antibody panel, which includes markers for glial, neural, epithelial and lymphoid differentiation antigens, was used to test a wide variety of cerebral and spinal tumours by indirect immunofluorescence and immunoperoxidase techniques on unfixed frozen sections. Gliomas, meningiomas, schwannomas, medulloblastomas, choroid plexus tumours, cerebral lymphomas and metastatic carcinomas could all be reliably differentiated by means of their characterisctic antigenics profiles, as defined by their patterns of reactivity with the antibody panel. Confident diagnosis was possible even in very poorly differentiated tumours and in biopsies distorted by surgical squeeze artefact, where paucity of morphological clues made diagnosis by conventional histological methods difficult or impossible. It was estimated that use of the antibody panel was responsible for, or made a significant contribution towards the final diagnosis in approximately 20% of cases.The monoclonal reagents were also found to be of great value in the detection and characterisation of neoplastic cells in CSF specimens from patients with malignant meningitis. Malignant cells were detected in 73% of cases and characterised in 16% of cases by routine cytological techniques. Employing monoclonal immunocytology however, these figures were improved to 95% and 95% respectively. Our findings suggest that patients with neoplastic meningtitis can be spared prolonged investigation and inappropriate management by the early detection and characterisation of malignant cells in CSF using panels of monoclonal antibodies.     

The diagnostic value of immunoglobulin G in the cerebrospinal fluid of brain tumor patients, particularly in malignant tumors

The diagnostic value of immunoglobulin G in cerebrospinal fluid (CSF-IgG) has been evaluated in patients with brain tumors. The (CSF-IgG) level in patients with malignant brain tumors was found to be significantly elevated when compared to the level in control patients without a disorder of the central nerve system. Especially significant was high level of CSF-IgG found in patients whose tumor had invaded into ventricles. The CSF-IgG level was found to decrease to a normal range by a total or subtotal resection of the tumor, but not by partial resection. On the other hand, CSF which contained large amount of IgG inhibited the lymphocyte proliferative response to phytomitogen. These results suggest that CSF-IgG seems to correlate with the tumor volume, and is important as a tumor marker in patients with a malignant brain tumor.     

Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell lines and primary tumor samples.

Prognosis for astroglial brain tumors that are not amenable to surgical resection remains poor. Consequently, a need to identify new cellular targets and chemotherapeutics for the treatment of astroglial tumors remains. Important reports indicate that human astroglial cell lines express higher protein kinase C (PKC) activity in comparison to normal astrocytes. PKC designates a family of kinases that regulate many cellular functions including cell growth and differentiation. The tight regulation of PKC activity is crucial for maintaining normal cellular proliferation since excessive activity leads to uncontrolled growth and cellular transformation. PKCepsilon, one of the 11 known PKC isozymes, has been shown to function as an oncogene in rodent fibroblasts by enhancing c-Raf-1 kinase activity leading to the stimulation of mitogen-activated protein (MAP) kinase pathway. We recently demonstrated that the ability of substance P (SP) neuropeptide to activate MAP kinase pathway in U-373MG astrocytoma cells correlates with its ability to selectively translocate PKCepsilon from cytosolic to membrane fraction, and that PKC inhibitors (e.g. CGP 41251) inhibit the activation of this pathway by SP or the PKC activator 12-O-tetradecanoyl phorbol 13-acetate (TPA). In this study, we demonstrated that PKCepsilon is overexpressed in many astroglial cell lines (n=27 lines), thus providing new evidence as to the possible involvement of this isozyme in the pathology of astroglial tumors. Consistently, we demonstrated that PKCepsilon is overexpressed in primary pediatric anaplastic astrocytoma (grade III) tumor samples as well as in cell lines derived from them, and that glioblastoma multiforme (grade IV) and gliosarcoma tumor samples, but not pilocytic astrocytomas (grade I), also express high levels of PKCepsilon. Therefore, the reported increase in PKC activity in brain tumor derived cell lines may be, in part, attributed to the overexpression of PKCepsilon and possibly other PKC isozymes. Consequently, we propose that the use of PKCepsilon selective inhibitors may be beneficial in the treatment of astroglial brain tumors.     

Vision-related quality-of-life in pediatric primary brain tumor patients

Journal of Neuro-Oncology - Brain tumors are the leading cause of death from childhood cancer. Although overall survival has improved due to earlier detection, better therapies, and improved...     

Elevated cerebrospinal fluid fibronectin concentration at diagnosis indicates poor prognosis in children with acute lymphoblastic leukemia

We investigated whether the concentration of fibronectin (FN) in the cerebrospinal fluid (CSF) could be used for identifying patients with subclinical blast-cell infiltration in the central nervous system (CNS) and an increased risk of CNS relapse later in the course of their leukemia. Our series comprised 36 children with newly diagnosed acute lymphoblastic leukemia (ALL). The mean follow-up time was 54 months (range 5 to 96 months). The median concentration of CSF-FN at diagnosis was 2.24 mg/l (range 0.78 to 7.04 mg/l). The 3-year continuous complete remission rate for the 16 patients with CSF-FN concentrations less than or equal to 2 mg/l was 93% as compared with 37% for the 19 patients with CSF-FN greater than 2 mg/l (p = 0.001). When multivariate analysis was performed, the CSF-FN concentration retained its prognostic significance. When all relapses were considered as failures, the relative risks of relapse for patients with CSF-FN less than or equal to 2 mg/l and greater than 2 mg/l were I and 15.8 (95% confidence limits 1.8-135.6, p less than 0.02), respectively. If only CNS relapses (isolated and combined) were considered as failures, relative risks for the above-mentioned groups were I and 11.6 (1.4-99.5, p less than 0.05), respectively. We conclude that determination of the CSF-FN concentration may provide a new means of evaluating the CSF in children with ALL and may prove to be a sensitive indicator of leukemic CNS infiltration.     

Serotonin and kinins in the cerebrospinal fluid in brain tumors]

Concentrations of serotonin, 5-hydroxyindoleacetic acid, melatonin and parameters of the kinin system in the cerebrospinal fluid were monitored in 109 cases of brain tumor. All the levels were increased prior to surgery but returned to normal postoperatively unless disease followed an unfavorable course. It was suggested that the above-mentioned physiologically active substances play a certain role in compensatory mechanisms assuring recovery of CNS function.     

Malignant pediatric brain tumor of primitive small round cell proliferation with bland-looking mesenchymal spindle cell elements

It is often difficult to classify rare malignant pediatric mixed brain tumors composed of mesenchymal elements. A 6-year-old boy presented to our hospital with a left frontal massive tumor manifesting as complaints of rapidly progressive right hemiparesis and motor aphasia over 2 weeks. Computed tomography showed a left frontal mass with thick calcification. Magnetic resonance imaging revealed an enhanced lesion with perifocal edema and mass effect. Total removal of the tumor was performed. Histological examination of the resected tumor revealed an anaplastic malignant small round cell component with a bland-looking mesenchymal spindle cell component. The patient was treated with irradiation to the whole craniospinal axis and a boost to the tumor bed, followed by chemotherapy consisting of ifosfamide, cisplatin, and etoposide, resulting in good control without local recurrence or metastasis at 2 years. A combined malignant tumor composed of ectodermal and mesenchymal components is generally named malignant ectomesenchymoma (MEM). The more malignant part of MEM is the mesenchymal component in most cases. In the present case, the more malignant component was not the mesenchymal component, but the small round cells.