Photodynamic therapy of malignant brain tumours

Fifty patients with malignant supratentorial tumours were treated with intra-operative photodynamic therapy (PDT); in 33 cases the tumour was recurrent. In 45 patients the tumour was a cerebral glioma and in 5 cases a solitary cerebral metastasis. All patients received a porphyrin photosensitizer 18-24 hours pre-operatively. Photoillumination was carried out at 630 nm to a tumour cavity created by radical tumour resection and/or tumour cyst drainage. The light energy density ranged from 8 to 175 J/cm2. In 8 patients additional interstitial light was administered. The operative mortality was 4%. Follow up has ranged from 1 to 30 months. The median survival for the 45 primary malignant tumours was 8.6 months with a 1 and 2 year actuarial survival rate of 32% and 18%, respectively. In 12 patients a complete or near complete CT scan response was identified post PDT. These patients tended to have a tumour geometry (eg. cystic) that allowed complete or near complete light distribution to the tumour. The median survival for this group was 17.1 months with a 1 and 2 year actuarial survival of 62% and 38%, respectively. In the 33 cases who did not have a complete response the median survival was 6.5 months with a 1 and 2 year actuarial survival of 22% and 11%, respectively. Photodynamic therapy of malignant brain tumours can be carried out with acceptable risk. Good responses appear to be related to adequate light delivery to the tumour.     

Presence of immunoreactive beta-endorphin in human brain tumor cyst fluids

The authors report the muscular and humoral immunological abnormalities found in a family with progressive external ophthalmoplegia (PEO) of the “pure” form. Serum circulating immune complexes as determined by the polyethylen glycol (PEG) test and double radial immunodiffusion (DRID) were positive for IgG in both cases studied and for IgM and Clq for the propositus. In the latter circulating auto-antibodies against smooth muscle were also present. Immunohistochemical studies on striated muscle of the propositus showed positive perivascular IgG and IgM staining and IgG in the sarcolemma-basement membrane complex. It is suggested that in this family a genetically inherited abnormal immune response to the muscular blood vessel wall has induced vascular injury and ultimately chronic ischemic muscular damage. This is consistent with the view that PEO is a clinical syndrome, i.e. the expression of various defects affecting primarily or secondarily the energy metabolism of the muscular tissue.     

Elevation of serum ceruloplasmin levels in brain tumours

Serum ceruloplasmin levels have been estimated in 80 patients with various intracranial space occupying lesions and in 30 controls. The ceruloplasmin levels were significantly increased in all brain tumours except in meningiomas. After therapy, the ceruloplasmin levels were still significantly increased when compared to controls and their respective preoperative values. However, the rise in levels of ceruloplasmin in malignant tumours compared to benign was statistically not significant. It is concluded that ceruloplasmin may have a role to play as an acute phase reactant protein in brain tumours.     

Elevated nitric oxide levels in childhood brain tumors

OBJECTIVES: One of the fundamental aspects of nitric oxide (NO) is the regulation of the inflammatory processes involved in neuronal apoptosis. Expressions of NO and NO synthase (NOS) are considered to be involved in brain tissue injuries and brain tumors. The purpose of our study was to investigate the roles of NO and inducible-form NOS (iNOS) in the pathogenesis of brain tumors. METHODS: NO levels in the cerebrospinal fluid (CSF) of 36 brain tumor patients were detected utilizing the NO-chemiluminescence method. Deparaffinized tissue sections were immunostained for the presence of antibodies against iNOS and for apoptosis using the TUNEL stain. The results were compared with 10 control patients (with epilepsy and hydrocephalus). CONCLUSIONS: Higher levels of NO and iNOS activities may induce immune responses and neurotoxicities. This preliminary study revealed elevated NO and NOS activities with an increased amount of apoptotic processes in brain tumor tissues, which may indicate the possible roles of NO in the formation of brain tumors.     

The neurodevelopmental price of survival in children with malignant brain tumours

Increasing survival rates in malignant brain tumors treatment have directed attention to the side effects of long-term disease control. Nevertheless, although the treatment protocols are continuously remodelled, the quality of life of children surviving for a long time is still poor. The most severe sequelae are neurocognitive disorders, which are associated with neurobehavioural alterations. The last are partly derived directly from the lesion localisation and treatments, but are often reinforced by academic and social failure. The deleterious effect of radiotherapy (CRT) is very well documented and confirmed in all the studies. The radiation dose delivered according to the age has reduced, but not fully eliminated, the negative influence on mental functioning. Also the CRT hyperfractionation has reduced, but not cancelled, this cognitive negative impact. Intrathecal methotrexate per se is responsible for a severe cognitive impairment, which can be even more severe in association to CRT. Some surgical approaches have been responsible for postoperative behavioural disturbances. Serial neuropsychological and behavioural evaluations, which should also include the survivors' own perception of their quality of life, are badly needed. The results of these evaluations should be covariate with several factors (age, type of surgery, lesion site, hydrocephalus, complementary therapies) in an attempt to define interdisciplinary treatment protocols to maximise survival while minimising cognitive/behavioural deficits.     

Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice

The brain levels of the endogenous excitotoxin quinolinic acid (QUIN) and its bioprecursor, the free radical generator 3-hydroxykynurenine (3-HK), are elevated in early stage Huntington disease (HD). We now examined the status of these metabolites in three mouse models of HD. In R6/2 mice, 3-HK levels were significantly and selectively elevated in the striatum, cortex and cerebellum starting at 4 weeks of age. In contrast, both 3-HK and QUIN levels were increased in the striatum and cortex of the full-length HD models, beginning at 8 months (YAC128) and 15 months (Hdh(Q92) and Hdh(Q111)), respectively. No changes were seen in 13-month-old shortstop mice, which show no signs of motor or cognitive dysfunction or selective neuropathology. These results demonstrate both important parallels and intriguing differences in the progressive neurochemical changes in these HD mouse models and support the hypothesis that QUIN may play a role in the striatal and cortical neurodegeneration of HD.     

The NG2 chondroitin sulfate proteoglycan: role in malignant progression of human brain tumours.

The expression and function of NG2, a transmembrane chondroitin sulfate proteoglycan was studied in human gliomas of various histological types in culture using immunocytochemistry and flow cytometry. NG2 was differentially expressed in the neoplasms, with higher expression in high compared to low-grade gliomas. In acutely isolated cells from human biopsies, NG2 +ve and NG2 -ve populations were morphologically distinct from each other, and NG2 +ve cells were more proliferative than NG2 -ve cells. The mitogens platelet derived growth factor (PDGF-AA) and basic fibroblast growth factor (bFGF) added in combination to serum-free medium (SFM) upregulated NG2 expression on glioblastoma multiforme cells in culture but had little effect on NG2 expression on the anaplastic astrocytoma cells. Furthermore, NG2 was colocalised with the platelet derived growth factor alpha receptor (PDGFalphaR) and antibody blockade of the PDGF-alphaR ablated NG2 expression on the glioblastoma multiforme cells, suggesting that increased NG2 expression in the presence of PDGF-AA is mediated via the PDGF-alphaR. Assays of migration and invasion indicate that NG2 +ve glioma cells migrated more efficiently on collagen IV and that NG2 -ve cells were more invasive than their NG2 +ve counterparts. The results indicate that NG2 may be, respectively, positively and negatively related to the proliferative and invasive capacity of glioma cells. Thus, expression of the NG2 proteoglycan may have major implications for malignant progression in glial neoplasms and may prove a useful target for future therapeutic regimens.     

Primary malignant rhabdoid tumours of brain, clinicoradiological findings of two cases

Malignant rhabdoid tumours (MRT) are extremely malignant, highly aggressive and uncommon renal neoplasms of childhood with very poor prognosis. About fifteen cases of primary intracranial MRT (with their clinical details) are reported in English literature, following the recognition of this entity in 1978. Two cases of MRT are reported here. The first case, one year male baby was admitted with a very large, infiltrative, posterior fossa mass. He required elective ventilation, following the tumour decompression but ultimately died of respiratory failure during the process of weaning from the ventilator. The second child was operated for an extremely vascular, very friable, solid and lobulated tumour of temporal lobe. Radical microsurgical decompression of mass was achieved, however the child developed massive recurrence, documented five weeks after the surgery while on radiotherapy. His recurrence showed partial response to radiotherapy and chemotherapy. The child is alive at 8 month's follow up, but probably passing the terminal days of his life. Hence the recognition of this entity is very essential for the aggressive management and prognostication of the patient, which obviously seems to be different from primitive neuroectodermal tumour.     

Head trauma and brain tumours revisited.

The authors report a case of an anaplastic astrocytoma which on magnetic resonance imaging and direct visualisation was continuous with an area of gliosis in the left frontal lobe. This gliosis was secondary to a head injury received 19 years earlier that required evacuation of an intracerebral haematoma. This case largely meets the accepted criteria for brain tumour associated with head trauma.     

Expression of AQP1 and AQP4 in paediatric brain tumours

Aquaporins (AQP) are water-channel proteins with roles in tumour cell migration, angiogenesis, cerebral oedema and cell-cell adhesion. We aimed to determine the expression of AQP1 and AQP4 in paediatric brain tumours. Twenty tumour bank specimens were subject to Western blot analysis and quantitative polymerase chain reaction (PCR) to determine the expression of AQP1 and 4. Immunohistochemical staining was used to determine the distribution of AQP1 and 4 expression. Medulloblastomas, primitive neuroectodermal tumour, germinomas and higher grade gliomas did not express AQP1 and 4. Of the ependymomas, those in the posterior fossa all demonstrated markedly increased expression of AQP1 and 4. A supratentorial ependymoma demonstrated a moderate increase in AQP1 but not AQP4. Pilocytic astrocytomas demonstrated high levels of AQP1 and 4 but had a more variable pattern of staining. AQP1 and 4 have relevance to paediatric brain tumours and are worthy of further investigation in developing potential therapeutic strategies.     

Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis

Background   Numerous studies have demonstrated elevated kappa free light chains (KFLCs) in CSF of multiple sclerosis (MS) patients. However, so far only small cohorts have been examined, and generally only through qualitative KFLCs analysis. Using a recently developed free light chain (FLC) immunoassay, it is now possible to quantitatively measure KFLCs by automated nephelometry. Our objective was to determine the extent to which KFLC levels in CSF correlated with the diagnosis of MS and CISSMS (clinically isolated syndrome suggestive of MS) compared to oligoclonal banding (OCB) and the immunoglobulin G (IgG) index. Methods   CSF and serum samples from 438 unselected patients, including a MS group of 70 patients (41 MS, 29 CISSMS), were analysed using nephelometry and isoelectric focusing. We then retrospectively correlated results with patients’ diagnoses. Results   Of the MS group (n = 70), 67 patients had elevated KFLCs using the KFLC index (≥ 5.9), 64 patients showed OCB and 56 patients presented with an elevated IgG index (≥ 0.6). Sensitivities were 0.96 for the KFLC index, 0.91 for OCB and 0.80 for the IgG index. The specificity of the KFLC index for the MS group (0.86) was lower than that of OCB (0.92) but distinctly higher compared to the IgG index (0.77). Conclusion   In this study, an elevated KFLC-index represented the most sensitive and specific quantitative diagnostic parameter for MS. As it is measured by automated, routinely available laboratory methods, KFLC quantitation can provide a rapid and reproduceable indication of intrathecal immunological processes supporting current MS diagnostic criteria. The study was performed in accordance with the ethical standards. An erratum to this article can be found at     

Imaging of iron oxide nanoparticles by MR and light microscopy in patients with malignant brain tumours

OBJECTIVE: Ferumoxtran-10 (Combidex), a dextran-coated iron oxide nanoparticle, provides enhancement of intracranial tumours by magnetic resonance (MR) for more than 24 h and can be imaged histologically by iron staining. Our goal was to compare ferumoxtran imaging and histochemistry vs. gadolinium enhancement in malignant brain tumours on preoperative and postoperative MR. METHODS: Seven patients with primary and metastatic malignant tumours underwent MR imaging with gadolinium and ferumoxtran both pre- and postoperatively. Normalized signal intensities on the ferumoxtran-enhanced scans were determined in representative regions of interest. Resected tissue from six ferumoxtran patients and from three patients who did not receive ferumoxtran was assessed for localization of iron in tumour and reactive brain. RESULTS: All malignant tumours (all of which enhanced by gadolinium MR) showed ferumoxtran accumulation with T1 and T2 signal changes, even using a 0.15 T intraoperative MR unit in one patient. Iron staining was predominantly in reactive cells (reactive astrocytes and macrophages) and not tumour cells. In five of the seven patients, including two patients who showed additional lesions, areas enhancing with ferumoxtran but not with gadolinium were observed. Comparison of the pre- and postoperative MR revealed residual ferumoxtran-enhancing areas in four of seven cases. CONCLUSION: In malignant tumours, ferumoxtran may show areas of enhancement, even with a 0.15 T intraoperative MR, that do not enhance with gadolinium. Ferumoxtran-enhancing lesions have persistent increased T1 signal intensity for 2-5 days, which may provide advantages over gadolinium for postoperative imaging. Histochemistry for iron shows uptake of ferumoxtran in reactive cells (astrocytes and macrophages) rather than tumour cells.     

Elevated levels of bilirubin and long-term exposure impair human brain microvascular endothelial cell integrity

The pathogenesis of encephalopathy by unconjugated bilirubin (UCB) seems to involve the passage of high levels of the pigment across the blood-brain barrier (BBB) and the consequent damage of neuronal cells. However, it remains to be clarified if and how the disruption of BBB occurs by UCB. We used confluent monolayers of human brain microvascular endothelial cells (HBMEC) to explore the sequence of events produced by UCB. A cell line and primary cultures of HBMEC were exposed to 50 or 100 μM UCB, in the presence of 100 μM human serum albumin, to mimic moderate and severe jaundice, for 1-72 h. UCB caused loss of cell viability in a concentration-dependent manner. UCB inhibited the secretion of interleukin-6, interleukin-8, monocyte chemoattractant protein-1 and vascular endothelial growth factor at early time points, but enhanced their secretion at later time points. Upregulation of mRNA expression, particularly by 100 μM UCB, preceded cytokine secretion. Other early events include the disruption of glutathione homeostasis and the increase in endothelial nitric oxide synthase expression followed by nitrite production. Prolonged exposure to UCB upregulated the expression of β-catenin and caveolin-1. In conclusion, elevated concentrations of UCB affect the integrity of HBMEC monolayers mediated by oxidative stress and cytokine release. UCB also induced increased expression of caveolin-1, which has been associated with BBB breakdown, and β-catenin, probably as an attempt to circumvent that impairment. These findings provide a basis for target-directed therapy against brain endothelial injury caused by UCB.     

Epilepsy and brain tumours in children

Although epilepsy is one of the clinical manifestations of brain tumour in one out of three children, such tumours are only found in 1 to 2% of epileptic children explored. When epilepsy reveals the tumour, the latter is benign in 9 out of 10 cases: usually an astrocytoma, an oligodendroglioma or a mixed oligoastrocytic tumour. These tumours accounted for 84% of benign tumours of the cerebral hemispheres among children treated by surgery in our department at the Enfants Malades hospital, Paris; 76% of them had been revealed by epileptic seizures. Among other lesions responsible for epilepsy were 2 cavernous angiomas and 6 thrombotic angiomas. Brain tumours were located in the temporal lobe in almost one half of the cases. The type of epileptic attack was variable, but complex partial seizures were the majority (47%). Several types were associated in 30% of the cases. Surgery was the only treatment in view of the very low recurrence rate. In 80% of the case, removal of the tumour was sufficient to suppress epilepsy. 71% of the children operated upon have an IQ of more than 80; 77% have normal schooling.     

心房颤动患者体内溶血磷脂类分子含量与无症状性脑梗死的相关性

目的 观察非瓣膜性心房颤动(NVAF)患者中无症状性脑梗死(SBI)的发病率及其血浆溶血磷脂类分子(LPA/AP)含量的变化,探索房颤相关性脑卒中的病理生理学机制,为临床进行抗栓治疗提供依据.方法 选取经临床和辅助检查确诊的235例未接受抗栓治疗的NVAF患者、116例无NVAF的SBI患者及120名年龄大于60岁的健康体检者纳入本研究.测定其血浆溶血磷脂酸(LPA)及其极性相似总磷脂(AP)的含量变化.同时观察NVAF合并SBI时体内血小板的活化状态.结果 235例NVAF患者中,SBI的发生率为31.5%,其中年龄大于60岁的157例NVAF患者中,SBI的发生率为37.6%.NVAF合并SBI患者血浆LPA含量[(3.78±0.61)μmol/L]显著高于对照组[(2.66±0.49)μmol/L,95%CI 3.47～4.21,P=0.000]、NVAF无SBI组[(3.29±0.57)μmol/L,95%CI 3.01～3.76,P=0.008]及无NVAF的SBI组[(3.17±0.54)μmol/L,95% CI2.86～3.54,P=0.004].NVAF无SBI组及无NVAF的SBI组血浆LPA含量也显著高于对照组.NVAF合并SBI患者血浆AP含量显著高于对照组、NVAF无SBI组及无NVAF的SBI组.NVAF无SBI组及无NVAF的SBI组血浆AP含量也显著高于对照组.与对照组相比,年龄大于60岁的NVAF患者合并存在SBI的比率显著升高.NVAF患者合并存在SBI时体内血小板的活化程度显著升高.结论 NVAF是SBI的重要危险因素.NVAF患者合并存在SBI时体内血小板的活化程度升高.NVAF或NVAF合并SBI患者均存在缺血性膜损伤.对于NVAF或合并SBI患者在进行抗栓治疗时应充分考虑抗血小板治疗的重要性.LPA可作为一种理想的分子标记物用于判断NVAF或NVAF合并SBI患者体内血小板的活化状态.