Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid of High-Grade Glioma Patients.

This work compares the metabolic profiles of plasma and the cerebrospinal fluid (CSF) of the patients with high-grade (III and IV) gliomas and the conditionally healthy controls using the wide-range targeted screening of low molecular metabolites by HPLC-MS/MS. The obtained data were analyzed using robust linear regression with Huber's M-estimates, and a number of metabolites with correlated content in plasma and CSF was identified. The statistical analysis shows a significant correlation of metabolite content in plasma and CSF samples for the majority of metabolites. Several metabolites were shown to have high correlation in the control samples, but not in the glioma patients. This can be due to the specific metabolic processes in the glioma patients or to the damaged integrity of blood-brain barrier. The results of our study may be useful for the understanding of molecular mechanisms underlying the development of gliomas, as well as for the search of potential biomarkers for the minimally invasive diagnostic procedures of gliomas.

Autologous and Pooled Tumor Lysates in Combined Immunotherapy of Patients with Glioblastoma.

Although major progress has been made in the standard treatment for glioblastomas, encompassing the maximal surgical resection, chemotherapy and radiation therapy, it is possible to increase survival rates significantly only in a few patients. Therefore, it is necessary to explore new therapeutic modalities, one of which is immunotherapy. The aim of the study was to evaluate the efficacy of the combined use of autologous and pooled tumor lysates in comprehensive treatment of patients with glioblastoma. MATERIALS AND METHODS: All patients (n=58, including 30 males and 28 females aged 18-70 years) were randomized into three groups, two of which received immunotherapy based on injection of autologous dendritic cells pulsed with autologous tumor lysates (first protocol) or pooled lysates (second protocol) from more than one tumor, in addition to the planned standard treatment. The patients of group 3 (control) received the standard comprehensive treatment encompassing the maximum safe tumor resection followed by radiation therapy and chemotherapy. RESULTS: The tolerability of both applied immunotherapy protocols was good: there were no anaphylactic reactions observed or patients who prematurely discontinued participation in the study. The final analysis of the data revealed no significant differences in median survival values of patients in each of the three groups. However, when analyzing the Karnofsky Performance Status in patients of group 2, it was found that it tended to improve. CONCLUSION: The study shows that the proposed immunotherapy protocols are safe for clinical use and have the potential to improve the patient's life quality. However, these findings should be considered intermediate until the findings of multicenter randomized clinical trials with a larger number of patients are obtained.

[Clinical results of basal meningiomas surgery with the neodymium laser]. / Rezul'taty khirurgii bazal'nykh meningiom s ispol'zovaniem neodimovogo lazera.

OBJECTIVE: to assess the efficacy of developed laser technologies of basal meningioma resection. MATERIAL AND METHODS: Authors analyzed the results of surgical treatment of 83 people, who underwent basal meningioma surgery in 1995-2008, in remote postoperative period. Follow-up and analysis of the dynamics of patient's quality-of-life, neurological deficit, frequency of relapses and continued growth of tumors were studied in 51 patients operated using neodymium laser and 32 patients after standard surgery. RESULTS AND CONCLUSION: The use of the neodymium laser in basal meningioma resection significantly increased the efficacy of surgery, reduced the risk of recurrent tumors and improved quality-of-life of patients in remote postoperative period.

[Cerebral actinomycotic granuloma mimicking malignant brain tumor].

We report a clinical case of cerebral actinomycotic granuloma that was preoperatively diagnosed as an intracerebral tumor. On the basis of a histological examination performed after lesion resection, the diagnosis of a cerebral actinomycotic granuloma was made. The article presents long-term outcomes of the surgery. The literature data on cases of various forms of cerebral actinomycosis are provided.

[Attention system functions and their relationship with self-reported health in patients with brain damage due to tumor].

AIM: To compare parameters of attention in healthy people and patients with neoplasms in different regions of the cerebral cortex and to evaluate quality of life (QoL) indices with regard to impairment of different attention systems. MATERIAL AND METHODS: Twenty patients with oncological lesions of the brain (mean age 56.5±8.8 years) who did not undergo surgery were studied. Tumor localization was confirmed using contrast-enhanced computed tomography, the tumor type was histologically verified. A control group included 18 healthy people matched for age, sex and education level. To determine attention system functions, we developed a computed version of the Attention Network Test. Error rate and reaction time for correct responses to the target stimulus, displayed along with neutral, congruent and incongruent signals, were the indicators of the efficacy of selective processes. QoL indices were assessed using SF-36 health survey questionnaire. RESULTS AND CONCLUSION: The readiness to respond to incoming stimuli was mostly impaired in patients with brain tumors. Efficacy of executive attention, assessed as the increase in the number of errors in selection of visual stimuli, was decreased while temporary parameters of the functions of this system were not changed in patients compared to controls. The SF-36 total score was stable in patients with marked reduction in scores on the Role and Emotional Functioning scales. The most severe health impairment measured on the SF-36 scales of role/social emotional functioning and viability was recorded in patients with the lesions of frontal cortical areas compared to temporal/parietal areas. The relationship between SF-36 Health self-rating and attention systems was found. This finding puts the question of the importance of attention characteristics and QoL for survival prognosis of patients with brain tumors.

CCL19/CCL21-Dependent Chemotaxis of Dendritic Cells in Healthy Individuals and Patients with Brain Tumors.

We compared migration activities of IFN-α- and IL-4-induced dendritic cells (IFN-DC and IL4-DC) generated from blood monocytes of healthy donors and analyzed migration activity of IFN-DC from patients with brain tumors. In the presence of CCL19 chemokine, donor IFN-DC exhibited higher migration activity than IL4-DC, the expression of chemokine CCR7-receptor being similar in the two cell types. IFN-DC of patients with malignant gliomas were characterized by low chemotaxis in response to CCL19 and CCL21 stimulation despite a trend to higher expression of CCR7 in comparison with donor IFN-DC.

[Cognitive functions and personality traits in patients with brain tumors: the role of lesion localization].

Personality traits and cognitive functions were studied depending on a tumor localization in the brain in 21 neurosurgical patients and the results were compared with a control group. In patients with brain damage, mostly affected were personality traits associated with emotion regulation and social interaction (neuroticism, psychoticism and social conformity). Increases in psychoticism and decreases in neuroticism were more expressed in patients with a left-hemisphere localization of tumors. The tumor-induced decrease in cognitive abilities was more presented in performing figurative tasks and less in verbal ones. Verbal functions were more decreased in the group with frontal localization of tumor compared to that with parietal localization.

[Intelligence and creativity changes induced by pathological growth of space-occupying cerebral lesion].

Creativity and intelligence changes depending on tumor localization in frontal or parietal cortex before surgical procedure in 24 patients in comparison with control group are studied. Brain damage-induced intelligence impairment and a decrease of fluency, flexibility of figural divergent thinking, and originality of verbal one without specificity of tumor localization were found. Intelligence decrease was more presented while performing of figural tasks and least of all in verbal ones. The left prefrontal brain damage induced a decrease of all components of intelligence and a trend to a decrease of verbal creativity and figural fluency. The right parietal brain lesion was more associated with a decline of divergent thinking originality.

Mesenchymal cells in the treatment of focal brain injury induced by venous circulation disturbances in rats.

We studied the efficiency of bone marrow multipotent mesenchymal stem cells for correction of neurological deficit in rats with experimental sustained focal brain injury caused by venous outflow disturbances. It was found that neurological deficit in animals with transplantation of multipotent mesenchymal stromal cells decreased by 54-75% (vs. 14-17% in the control group) by day 21. The efficiency of mesenchymal stromal cell transplantation (intravenous or local) on day 1 of postoperation period was significantly higher than on day 7. This manifested in more pronounced decrease in the severity of neurological disorders (according to modified neurological severity score) and more rapid recovery of autonomic feeding. Moreover, transplantation of multipotent mesenchymal stromal cells on day 1 abolished the need in antiedematous therapy, while in animals receiving cell therapy on day 7, administration of glucocorticoids was necessary. Comparison of two regimens of cell administration at early terms revealed no advantages of local transplantation of multipotent mesenchymal stromal cells over intravenous injection.

Use of interferon-alpha-induced dendritic cells in the therapy of patients with malignant brain gliomas.

Clinical and immunological analysis of the efficiency of combined immunotherapy with the use dendritic cells for the treatment of malignant glioma of the brain was carried out. Dendritic cells generated in the presence of granulocyte-macrophage CSF and IFN-alpha retain their functional characteristics in patients with gliomas, which suggests the possibility of their use for the treatment of malignant tumors (glioma) of the brain. Combined therapy using interferon-induced dendritic cells was associated with generation of antigen-specific immune response during vaccinations. The results indicate satisfactory tolerance of combined immunotherapy using dendritic cells and the absence of toxic side effects at the stage of adoptive immunotherapy and at the stage of vaccinations with dendritic cells. Clinical trials showed that vaccinations with dendritic cells included into combined immunotherapy improved the quality of life and survival of patients with malignant gliomas.

Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients.

We studied the safety and efficiency of transplantation of autologous bone marrow cells in complex therapy of patients with spinal cord injury in the late period of the disease. In control group patients, meningomyeloradiculolis was performed, while in the main group surgical treatment was supplemented by transplantation of autologous bone marrow cells. Transplantation of BM stem cells into the cyst cavity and intravenously was well tolerated, did not cause allergic or inflammatory reactions in the early and delayed periods after surgery, and did not induce the formation of ossification foci in the nervous tissue. Analysis of the neurological status by ASIA, Bartel, and Ashworth scales showed that in the main group the positive clinical dynamics was more often observed than in the control. The decrease in neurological deficit included improvement of sensory and motor activity and conducting sensory function. Thus, transplantation of autologous bone marrow cells can be a novel safe strategy for the treatment of patients in the late period after spinal trauma.

Characteristics of bone marrow cells under conditions of impaired innervation in patients with spinal trauma.

We studied quantitative and functional parameters of bone marrow stem cells and mature lymphocyte population under conditions of impaired innervation in patients with injuries to the cervical and thoracic portions of the spinal cord. Our findings indicated the absence of deficiency of quantitative and proliferative potentials of stem cells and demonstrated intact subpopulation structure of mature lymphocytes and T-cell proliferative activity similar to that in donors. The content of CD34+ cells in patients did not differ from that in donors. The percentage of CD34+CD38- hemopoietic stem cells was elevated in patients, presumably due to increased proliferative activity of hemopoietic stem cells. The possibility of derivation and in vitro culturing of fibroblast-like cells with mesenchymal stem cell phenotype was demonstrated.

[Antigen-specific immunotherapy as a component of combined therapy for malignant brain tumors]. / Antigenspetsificheskaia immunoterapiia v kompleksnom lechenii bol'nykh zlokachestvennymi opukholiami golovnogo mozga.

The purpose of the present research was to study immunity in the course of complex treatment for malignant gliomas of the brain and to evaluate extracorporeal antigen-specific immunotherapy (EASIT), a pilot procedure which was carried out according to an approved protocol. Initially, lowered HLA-DR+ monocyte count and in vitro inhibition of proliferative activity were reported in all patients. Inductive EASIT started in early postoperative period aborted immune disturbances caused by surgery. In 1998-2000, the procedure was performed in 33 patients with anaplastic astrocytoma (AA) (20) and glioblastoma (GB) (13). Mean dose of cell infusion was 2.43(0.18 x 109/patient and was well tolerated. There are 22 survivors and 9 patients died (GB--4 and AA--5; overall mortality--29%). Mean relapse-free survival was 14.2 mo (22); stable remission during 12-18 mo--37.5% (3/8)(GB) and 64% (9/14) (AA) Complete rehabilitation of immunity was generally reported 12 mo after the course of EASIT. Hence, complex treatment (surgery + EASIT) enhanced its efficacy in the management of brain tumors.

[Characteristics and immunologic changes in patients with malignant brain tumors]. / Kharakteristika i mekhanizmy immunnykh narushenii u bol'nykh so zlokachestvennymi opukholiami golovnogo mozga.

The investigation was concerned with assaying immunity and evaluating the role played by monocytes and tumor cells in the formation of T-cell dysfunction in malignant glioma (MG). The study group included 28 patients with anaplastic astrocytomas (n = 18) and glioblastomas (n = 10). MG patients showed significant changes in the numbers of CD16+ NK-cells and HLA-DR monocytes as well as lowered levels of HLA-DR expression on monocytes and proliferative response of T-lymphocytes as compared with both standard and alternative pathways of activation. Monocytes and macrophages suppressed T-cell activity due to production of prostaglandins E2 in such patients. Enhanced immunosuppression was also reported in 24-hour supernatants of tumor cells. Immune disorders were shown to involve apoptosis-independent mechanisms. Hence, despite the immune privilege of the brain, immunocompetent cells crossed blood-brain barrier and counteracted with tumor cells. As a consequence, monocyte function and cellular cooperation dropped while production of immunosuppressive factors rose, and T-cell dysfunction was brought about through apoptosis-independent mechanisms.

[The possibility of immunocorrection in spinal-spinal cord trauma by using intravenous laser irradiation]. / Vozmozhnost' immunokorrektsii pri pozvonochno-spinnomozgovoi travme s pomoshch'iu vnutrivennogo lazernogo oblucheniia.

The natural defense factors of the body and the cell factors of immunity were studied in 60 patients with acute and early spinal trauma. Immunodeficiency develops in 100% of cases with acute and early spinal trauma. Blood intravenous laser radiation at wave lengths of 632 and 830 nm was shown to produce an immunostimulating effect.

[Changes in the cellular immunity factors in suppurative complications of penetrating craniocerebral trauma]. / Izmenenie faktorov kletochnogo immuniteta pri gnoinykh oslozhneniiakh pronikaiushchei cherepno-mozgovoi travmy.

The authors examined patients with penetrating cerebrocranial trauma (CCT) and uneventful course of traumatic disease (30) and those with CCT complicated by intracranial purulent process (24 persons). A direct correlation of the marked character and severity of the clinical course of the posttraumatic period and the changes in the immune system was revealed. Increase of the level of neutrophil rosette formation, indices of the NST test, the activity and intensity of neutrophil phagocytosis in penetrating CCT allows the development of an intracranial purulent process to be predicted at an early stage before the appearance of clinical sings. Decrease of the number of spontaneous rosette-forming and formazan-positive neutrophils is an indication of an unfavourable course of an intracranial purulent complication with a fatal outcome.

[The experimental and clinical use of gelatin sponges with kanamycin and gentamycin for the prevention and treatment of suppurative complications in neurosurgery]. / Eksperimental'noe i klinicheskoe primenenie zhelatinovykh gubok s kanamitsinom i gentamitsinom dlia profilaktiki i lecheniia gnoinykh oslozhnenii v neirokhirurgii.

Antiseptic gelatin sponges with kanamycin and gentamicin, which were studied in experiments on animals and used in the clinic, are a reliable measure for the prevention of suppuration in craniocerebral surgery in planned operations and in combination with debridement in penetrating injury of the skull and brain. For therapeutic purposes, local application of the agents is effective in focal suppurative processes in the skull and brain after surgical debridement of the purulent focus (abscess of the brain, osteomyelitis of the skull, etc.).