Minoru Shigemori

Optimal temperature for the management of severe traumatic brain injury: effect of hypothermia on intracranial pressure, systemic and intracranial hemodynamics, and metabolism.

OBJECTIVEWe studied the effect of hypothermia on intracranial pressure, systemic and intracranial hemodynamics, and metabolism in patients with severe traumatic brain injury to clarify the optimal temperature for hypothermia, with a view toward establishing the proper management techniques for such patients. METHODSThe study was performed in 31 patients with severe head injury (Glasgow Coma Scale score as high as 5). All patients were sedated, paralyzed, ventilated, and cooled to 33°C. Brain temperature, core temperature, intracranial pressure, cerebral perfusion pressure, jugular venous oxygen saturation, mixed venous oxygen saturation, cardiac output, oxygen delivery, oxygen consumption, and resting energy expenditure were monitored continuously. RESULTSIntracranial pressure decreased significantly at brain temperatures below 37°C and decreased more sharply at temperatures 35 to 36°C, but no differences were observed at temperatures below 35°C. Cerebral perfusion pressure peaked at 35.0 to 35.9°C and decreased with further decreases in temperature. Jugular venous oxygen saturation and mixed venous oxygen saturation remained in the normal range during hypothermia. Resting energy expenditure and cardiac output decreased progressively with hypothermia. Oxygen delivery and oxygen consumption decreased to abnormally low levels at rectal temperatures below 35°C, and the correlation between them became less significant at less than 35°C than that when temperatures were 35°C or higher. Brain temperature was consistently higher than rectal temperature by 0.5 ± 0.3°C. CONCLUSIONThese results suggest that, after traumatic brain injury, decreasing body temperature to 35 to 35.5°C can reduce intracranial hypertension while maintaining sufficient cerebral perfusion pressure without cardiac dysfunction or oxygen debt. Thus, 35 to 35.5°C seems to be the optimal temperature at which to treat patients with severe traumatic brain injury.

Immunologic Evaluation of Personalized Peptide Vaccination for Patients with Advanced Malignant Glioma

Purpose: The primary goal of this phase I study was to assess the safety and immunologic responses of personalized peptide vaccination for patients with advanced malignant glioma. Experimental Design: Twenty-five patients with advanced malignant glioma (8 grade 3 and 17 grade 4 gliomas) were evaluated in a phase I clinical study of a personalized peptide vaccination. For personalized peptide vaccination, prevaccination peripheral blood mononuclear cells and plasma were provided to examine cellular and humoral responses to 25 or 23 peptides in HLA-A24+ or HLA-A2+ patients, respectively; then, only the reactive peptides (maximum of four) were used for in vivo administration. Results: The protocols were well tolerated with local redness and swelling at the injection site in most cases. Twenty-one patients received more than six vaccinations and were evaluated for both immunologic and clinical responses. Increases in cellular or humoral responses specific to at least one of the vaccinated peptides were observed in the postvaccination (sixth) samples from 14 or 11 of 21 patients, respectively. More importantly, significant levels of peptide-specific IgG were detected in the postvaccination tumor cavity or spinal fluid of all of the tested patients who showed favorable clinical responses. Clinical responses were 5 partial responses, 8 cases of stable disease, and 8 cases of progressive disease. The median overall survival for patients with recurrent glioblastoma multiforme in this study (n = 17) was 622 days. Conclusions: Personalized peptide vaccinations were recommended for the further clinical study to malignant glioma patients.

Therapeutic effect and mechanism of repetitive transcranial magnetic stimulation in Parkinson's disease

Abstract The therapeutic effect of repetitive transcranial magnetic stimulation (rTMS) on clinical performance was assessed by a double-blind study in 9 patients with Parkinsons disease (PD). Nine other patients underwent sham stimulation as controls. The modified Hoehn and Yahr (H&Y) staging scale, the Schwab and England Activities of Daily Living (ADL) scale, and the Unified Parkinsons disease rating scale (UPDRS) were used to assess changes of clinical performance. Patients were assessed prior to and following 2 months of rTMS. In addition, the mechanism of rTMS was investigated by dopamine and homovanillic acid (HVA) in the lumbar cerebrospinal fluid (CSF) of 17 patients before and after therapeutic rTMS for three or four months. rTMS was applied manually to the frontal areas 60 times per session, i. e., 30 times per side using a large circular coil, a pulse intensity of 700 V, and a frequency of 0.2 Hz. Sessions were continued once a week for 2 months. The 9 control patients showed no changes of symptoms between the initial evaluation and that after 2 months of sham rTMS. In contrast, all 9 patients receiving rTMS showed a significant decrease of the modified H&Y and UPDRS scores after 2 months, while the Schwab and England ADL Scale scores increased significantly. In the second CSF sample from patients receiving rTMS, HVA showed a significant decrease These results suggest that rTMS is beneficial for the symptoms of Parkinsons disease and that it may act via inhibition of dopaminergic systems.

Effect of 35°C Hypothermia on Intracranial Pressure and Clinical Outcome in Patients With Severe Traumatic Brain Injury

BACKGROUND From 1994, we have used therapeutic hypothermia in patients with severe traumatic brain injury (Glasgow Coma Scale scores of 5 or less). In 2000, we altered the target temperature to 35 degrees C from the former 33 degrees C, as our findings suggested that cooling to 35 degrees C is sufficient to control intracranial hypertension, and that hypothermia below 35 degrees C may predispose patients to persistent cumulative oxygen debt. We attempted to clarify whether 35 degrees C hypothermia has the same effect as 33 degrees C hypothermia in reducing intracranial hypertension and whether it is associated with fewer complications and improved outcomes. METHODS We compared intracranial pressure (ICP) and biochemical parameters in the 30 patients treated with 35 degrees C hypothermia (January 2000 to June 2005) with those in the 31 patients treated with 33 degrees C hypothermia (July 1994 to December 1999). RESULTS Patient characteristics were similar in the two groups. The mean temperature during hypothermia was 35.1 +/- 0.7 degrees C in the 35 degrees C hypothermia group and 33.4 +/- 0.8 degrees C in the 33 degrees C hypothermia group. Mean ICP was controlled under 20 mm Hg during hypothermia in both the 35 degrees C hypothermia and 33 degrees C hypothermia groups. The incidence of intracranial hypertension and low cerebral perfusion pressure did not differ between the two groups. The 35 degrees C hypothermic patients exhibited a significant improvement in the decline of serum potassium concentrations during hypothermia and in the increment of C-reactive protein after rewarming. The mortality rate and the incidence of systemic complications tended to be lower in the 35 degrees C group. CONCLUSIONS Cooling patients to 35 degrees C is safe and the ICP reduction effects of 35 degrees C hypothermia are similar to those of 33 degrees C hypothermia.

Age-Associated Increases in Poor Outcomes after Traumatic Brain Injury: A Report from the Japan Neurotrauma Data Bank

Age is an important factor influencing outcome after severe traumatic brain injury (TBI). In general, the older the victim, the higher the probability of a poor outcome. To investigate the mechanism underlying the link between age and outcome, the data for 797 patients enrolled in the Japan Neurotrauma Data Bank (JNTDB), aged 6 years or older, with Glasgow Coma Scale (GCS) scores of 8 or less on admission or deterioration to that level within 48 h of impact were analyzed. Thirty-eight percent of the patients were between the ages of 40 and 69 years, and 24% of the patients were older than 69 years. Older patients had higher rates of mortality and lower rates of favorable outcome. The frequency of mass lesions which were associated with poorer outcomes significantly increased with age, but regardless of the intracranial lesion type, older patients had poorer outcomes. The GCS score and the occurrence of systemic complications did not differ significantly according to age. Multiple systemic injury was less frequent in older patients. The varied occurrence of intracranial lesion types according to age is likely caused by the disparity between the young and aged brain in the progression of secondary brain injury. Alteration in the pathophysiological response, which is related to the development of secondary brain injury in the aging brain, probably contributes to more severe and irreversible brain damage in older patients, and is thus associated with poor outcomes.

Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4

Aquaporin-4 (AQP4) plays a role in the generation of post-ischemic edema. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the central nervous system (CNS) associated with altered brain water balance. Edaravone, a free radical scavenger, is used for the treatment of acute ischemic stroke (AIS) in Japan. In this study, edaravone significantly reduced the infarct area and improved the neurological deficit scores at 24h after reperfusion in a rat transient focal ischemia model. Furthermore, edaravone markedly reduced AQP4 immunoreactivity and protein levels in the cerebral infarct area. In light of observations that edaravone specifically inhibited AQP4 in a rat transient focal ischemia model, we propose that edaravone might reduce cerebral edema through the inhibition of AQP4 expression following cerebral infarction.

Expression of the SART3 tumor-rejection antigen in brain tumors and induction of cytotoxic T lymphocytes by its peptides.

The authors recently reported on the SART3 tumor-rejection antigen, which possesses epitopes that can induce cytotoxic T lymphocytes (CTLs) in patients with epithelial cancer. To explore a new modality for treatment of patients with brain tumors, this study investigated the expression of the SART3 antigen in patients with brain tumors and the ability of SART3 peptides to induce CTLs from peripheral blood mononuclear cells (PBMCs) of these patients. The SART3 antigen was detected in the cytoplasmic fraction of all 18 glioma cell lines examined and in the majority (31 of 34; 91%) of brain tumor tissues irrespective of their histologies. It was also expressed in the nuclear fraction of all 18 glioma cell lines and in the majority (26 of 34; 76%) of brain tumor tissues. In contrast, the SART3 was not expressed in nontumorous brain tissues. Cytotoxic T lymphocytes were induced in patients with glioma by stimulation with two epitope peptides of SART3. These CTLs could eliminate glioma cells in a HLA-A24–restricted manner. Therefore, the SART3 peptides may be appropriate molecules for use in peptide-based specific immunotherapy of HLA-A24+ patients with brain tumors.

Expression of the tumor-rejection antigen SART1 in brain tumors.

We have reported a tumor‐rejection antigen, SART1259, possessing tumor epitopes capable of inducing cytotoxic T lymphocytes (CTLs) in epithelial‐cancer patients. This study investigated the expression of SART1259 antigen in brain tumors, to explore for a potential molecule for use in specific immunotherapy of patients with brain tumors. The SART1259 antigen was detected in the cytosol fraction of 13 of 18 (72%) glioma cell lines and in 12 of 34 (35%) brain‐tumor tissues, with a higher rate of expression among malignant gliomas (5/10, 50%) and schwannomas (3/4). HLA‐A24‐restricted and SART1‐specific CTLs recognized the HLA‐A24+ and SART1259+ glioma cells, and the levels of recognition correlated both with HLA‐A24‐antigen expression level and with the concentration of the SART1 peptide antigen. Therefore, the SART1259 antigen could be a target molecule for specific immunotherapy of patients with brain tumors expressing HLA‐class‐I antigens. Int. J. Cancer 83:760–764, 1999.

CXCL12/CXCR4 signaling in malignant brain tumors: a potential pharmacological therapeutic target

Chemokines are 8- to 12-kDa peptides that function as chemoattractant cytokines involved in cell activation, differentiation, and trafficking. Chemokines bind to specific G-protein-coupled, seven-span transmembrane receptors on the plasma membrane of target cells. Chemokine (C-X-C motif) ligand 12 (CXCL12), an alpha-chemokine that binds to G-protein-coupled chemokine (C-X-C motif) receptor 4 (CXCR4), plays an important and unique role in the regulation of stem/progenitor-cell trafficking. As CXCR4 is expressed on several cancer cells, these CXCR4-positive cancer cells may metastasize to organs that secrete/express CXCL12. Regarding brain tumors, recent data demonstrate that glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via the CXCL12/CXCR4 pathway. In addition, CXCL12/CXCR4 have recently been shown to be expressed in primary central nervous system (PCNS) lymphomas, and a role for chemokines in the pathogenesis of PCNS lymphomas was suggested. This review focuses on current knowledge regarding the biology of the CXCL12/CXCR4 pathway in the context of understanding their potential role in malignant gliomas and PCNS lymphoma development. The CXCL12/CXCR4 interaction as a therapeutic target for malignant brain tumors is also discussed.

The Free Radical Scavenger Edaravone Rescues Rats from Cerebral Infarction by Attenuating the Release of High-Mobility Group Box-1 in Neuronal Cells

Edaravone, a potent free radical scavenger, is clinically used for the treatment of cerebral infarction in Japan. Here, we examined the effects of edaravone on the dynamics of high-mobility group box-1 (HMGB1), which is a key mediator of ischemic-induced brain damage, during a 48-h postischemia/reperfusion period in rats and in oxygen-glucose-deprived (OGD) PC12 cells. HMGB1 immunoreactivity was observed in both the cytoplasm and the periphery of cells in the cerebral infarction area 2 h after reperfusion. Intravenous administration of 3 and 6 mg/kg edaravone significantly inhibited nuclear translocation and HMGB1 release in the penumbra area and caused a 26.5 ± 10.4 and 43.8 ± 0.5% reduction, respectively, of the total infarct area at 24 h after reperfusion. Moreover, edaravone also decreased plasma HMGB1 levels. In vitro, edaravone dose-dependently (1–10 μM) suppressed OGD- and H2O2-induced HMGB1 release in PC12 cells. Furthermore, edaravone (3–30 μM) blocked HMGB1-triggered apoptosis in PC12 cells. Our findings suggest a novel neuroprotective mechanism for edaravone that abrogates the release of HMGB1.