Kimihiro Nagatani

Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas.

BACKGROUND xCT is a light chain of the cystine/glutamate antiporter system xc. Glutamate that is released by system xc plays an important role in the infiltration of glioblastoma (GBM) cells. Furthermore, increased glutathione synthesis by system xc may protect tumor cells against oxidative stress induced by radiotherapy and chemotherapy. OBJECTIVE To investigate whether the levels of xCT expression correlated with infiltrative imaging phenotypes on magnetic resonance imaging and outcomes in patients with GBMs. METHODS Forty patients with histologically confirmed primary GBMs were included in the study. Patient charts were retrospectively reviewed for age, sex, Karnofsky Performance Status Scale score, Mini-Mental State Examination score, magnetic resonance imaging features, xCT expression, isocitrate dehydrogenase 1 R132H expression, O-methylguanine-DNA methyltransferase promoter methylation status, type of surgery, progression-free survival, and overall survival. RESULTS In invasive margins, xCT expression was weak in 20 patients and strong in 20 patients. A Cox regression model revealed that a Karnofsky Performance Status Scale score less than 60 (hazard ratio [HR]: 4.525; P = .01), partial removal (HR: 2.839; P = .03), and strong xCT expression (HR: 4.134; P < .001) were significantly associated with shorter progression-free survival and that partial removal (HR: 2.865; P = .03), weak isocitrate dehydrogenase 1 R132H expression (HR: 15.729; P = .01), and strong xCT expression (HR: 2.863; P = .04) were significantly associated with shorter overall survival. CONCLUSION These findings suggest that xCT is an independent predictive factor in GBMs.

Decompressive hemicraniectomy for spontaneous intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is devastating, with high mortality rates, but its optimum management has not been fully established. Decompressive hemicraniectomy is a surgical procedure used to relieve the malignant elevation of intracranial pressure. The application of decompressive hemicraniectomy in patients with hemispheric ICH has been much less common, although several studies have shown the usefulness of this procedure for large hemispheric ICH. In this review, the present knowledge of the safety and efficacy of this procedure are evaluated. The authors conclude that decompressive hemicraniectomy with hematoma evacuation for large ICH might be a safe and effective procedure in patients with severely disturbed consciousness and large hematoma volume.

Effect of hydrogen gas on the survival rate of mice following global cerebral ischemia.

Global cerebral ischemia and reperfusion (I/R) often result in high mortality. Free radicals have been reported to play an important role in global cerebral I/R, and therefore, reduction of these might improve the outcome. Here, we investigated the effect of hydrogen gas (H2) (a strong free radical scavenger) on the survival rate of mice following global cerebral I/R. We further examined the histopathological outcome and also the brain water content (as a possible determinant of mortality). Male C57BL/6J mice were subjected to global cerebral I/R by means of 45-min bilateral common carotid artery occlusion (BCCAO). A total of 160 mice were divided into three groups: sham surgery (sham group), BCCAO without H2 (BCCAO group), and BCCAO treated with 1.3% H2 (BCCAO + H2 group). We observed that H2 treatment significantly (P = 0.0232) improved the 7-day survival rate of mice, from 8.3% (BCCAO group, n = 12) to 50% (BCCAO + H2 group, n = 10). Histopathological analysis revealed that H2 treatment significantly attenuated neuronal injury and autophagy in the hippocampal cornu ammonis 1 sector and also brain edema, after 24 h of reperfusion. The beneficial effects of H2 treatment on brain injury were associated with significantly lower levels of oxidative stress markers (8-hydroxy-2′-deoxyguanosine and malondialdehyde) in the brain tissue. Thus, we believe that H2 may be an effective treatment for global cerebral I/R. ABBREVIATIONS 8-OHdG—8-hydroxy-2′-deoxyguanosine BBB—blood-brain barrier BCCAO—bilateral common carotid artery occlusion CA1—cornu ammonis 1 CBF—cerebral blood flow I/R—ischemia and reperfusion LC3—microtubule-associated protein 1 light chain 3 MDA—malondialdehyde P-com A—posterior communicating artery ROS—reactive oxygen species

Decompressive craniectomy with hematoma evacuation for large hemispheric hypertensive intracerebral hemorrhage.

Hemispheric hypertensive intracerebral hemorrhage (ICH) has a high mortality rate. Decompressive craniectomy (DC) has generally been used for the treatment of severe traumatic brain injury, aneurysmal subarachnoid hemorrhage, and hemispheric cerebral infarction. However, the effect of DC on hemispheric hypertensive ICH is not well understood. To investigate the effects of DC for treating hemispheric hypertensive ICH, we retrospectively reviewed the clinical and radiological findings of 21 patients who underwent DC for hemispheric hypertensive ICH. Eleven of the patients were male and 10 were female, with an age range of 22-75 years (mean, 56.6 years). Their preoperative Glasgow Coma Scale scores ranged from 3 to 13 (mean, 6.9). The hematoma volumes ranged from 33.4 to 98.1 mL (mean, 74.2 mL), and the hematoma locations were the basal ganglia in 10 patients and the subcortex in 11 patients. Intraventricular extensions were observed in 11 patients. With regard to the complications after DC, postoperative hydrocephalus developed in ten patients, and meningitis was observed in three patients. Six patients had favorable outcomes and 15 had poor outcomes. The mortality rate was 10 %. A statistical analysis showed that the GCS score at admission was significantly higher in the favorable outcome group than that in the poor outcome group (P = 0.029). Our results suggest that DC with hematoma evacuation might be a useful surgical procedure for selected patients with large hemispheric hypertensive ICH.

Sulfasalazine and temozolomide with radiation therapy for newly diagnosed glioblastoma

BACKGROUND A recent phase 1/2 clinical trial argued for caution for the use of sulfasalazine in progressive glioblastoma (GBM). However, the study enrolled patients with recurrent or progressive high-grade glioma indicating that patients recruited probably had severe disease. Thus, the study may not accurately reflect the effectiveness of sulfasalazine for GBM and we hypothesized that earlier sulfasalazine administration may lead to anticancer effects. AIM The aim of this study was to investigate whether sulfasalazine can improve the outcomes of patients with newly diagnosed GBM. SUBJECTS AND METHODS A total of 12 patients were treated with temozolomide and sulfasalazine with radiation therapy after surgery. Twelve patients with primary GBM treated with temozolomide and radiation therapy formed the control group. Progression-free survival (PFS), overall survival (OS) and seizure-free survival (SFS) curves were obtained using the Kaplan-Meier method. The survival curves were compared using the log-rank test. RESULTS The median OS, PFS and SFS did not differ between the groups. Grade 3 or 4 adverse events occurred over the duration of the study in nine (75%) patients. The median SFS was 12 months in nine patients who received sulfasalazine administration for more than 21 days, which was strongly but not significantly longer than the 3 months observed in the control group (P = 0.078). CONCLUSIONS Sulfasalazine treatment with temozolomide plus radiotherapy for newly diagnosed primary GBM is associated with a high rate of discontinuation due to hematologic toxic effects. This treatment may have no effect on OS or PFS, although it may improve seizure control if an adequate dose can be administered.

Effects of intravenous infusion of hydrogen-rich fluid combined with intra-cisternal infusion of magnesium sulfate in severe aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial

BackgroundThe failures of recent studies intended to prevent cerebral vasospasm have moved the focus of research into delayed cerebral ischemia away from cerebral artery constriction towards other mechanisms. Recent accumulating evidence has suggested that early brain injury is also involved in the development of delayed cerebral ischemia, and that hydrogen can prevent early brain injury. Therefore, we have established a combination therapy of intravenous hydrogen infusion and intra-cisternal magnesium sulfate infusion for the treatment of both early brain injury and cerebral vasospasm. The present randomized controlled clinical trial is designed to investigate the effects of this novel therapeutic strategy on the occurrence of cerebral vasospasm, delayed cerebral ischemia, and clinical outcomes after high-grade subarachnoid hemorrhage.MethodsThis study is a randomized, double-blind, placebo-controlled design to be conducted in two hospitals. A total of 450 patients with high-grade subarachnoid hemorrhage will be randomized to one of three arms: (i) Mg + H2 group, (ii) Mg group, and (iii) control group. Patients who are assigned to the Mg + H2 group will receive intra-cisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days and intravenous hydrogen-rich fluid infusion (200 mL) twice a day for 14 days. Patients who are assigned to the Mg group will receive intra-cisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days and intravenous normal glucose-electrolyte solution (200 mL) without added hydrogen twice a day for 14 days. Patients who are assigned to the control group will receive intra-cisternal Ringer solution without magnesium sulfate at 20 mL/h for 14 days and intravenous normal glucose-electrolyte solution (200 mL) without added hydrogen twice a day for 14 days. Primary outcome measures will be occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary outcome measures will be modified Rankin scale score at 3, 6, and 12 months and biochemical markers.DiscussionThe present protocol for a randomized, placebo-controlled study of intravenous hydrogen therapy with intra-cisternal magnesium infusion is expected to establish the efficacy and safety of this therapeutic strategy.Trial registrationUMIN-CTR: UMIN000014696

Intravenous tissue plasminogen activator treatment for ischemic stroke in dabigatran-treated patients

Vergouwen et al. reported that intravenous tissue plasmin-ogen activator (IV tPA) treatment was not associated withan increased risk of secondary intracerebral hemorrhage orgastrointestinal hemorrhage in patients with acute ischemicstroke taking warfarin with an international normalizedratio (INR) <1.7 [6]. These results mean that IV tPAtreatment should not be discouraged in patients takingwarfarin with INR <1.7.Recently, dabigatran, a new oral anticoagulant, wasapproved by the FDA. In the Randomized Evaluation ofLong-Term Anticoagulant Therapy trial, dabigatran wasshown to be as effective as warfarin in prevention of systemicembolism and future stroke, with lower risk of majorhemorrhage [2]. Additionally, dabigatran does not needmonitoring (differently from warfarin). Therefore, the numberof dabigatran-treated patients presenting with ischemic strokemay increase in the future. However, there is no guidelinewhether dabigatran-treated patients presenting with ischemicstroke can be considered eligible for IV tPA treatment or not.Only two case reports demonstrated the safety of IV tPAtreatment for acute ischemic stroke in dabigatran-treatedpatient [3, 5]. On the other hand, Ammollo et al. reportedthat dabigatran enhanced the susceptibility of plasma clots totPA-induced lysis in in vitro study [ 1]. Based on Ammollo’sresults, we can hypothesize that dabigatran may also enhancethebleedingriskcausedbytPA.Although we recognize the lack of data on IV tPAtreatment for acute ischemic stroke in dabigatran-treatedpatients, we need provisional guidelines of the topic, asearly as possible, in order to avoid confusion. Some tests,such as activated partial thrombin time and ecarin clottingtime, which have been reported as correlated with dabiga-tran concentrations, can be helpful for clinicians todetermine the indication of IV tPA for such patients [4].

Temporal profile of plasma adiponectin level and delayed cerebral ischemia in patients with subarachnoid hemorrhage.

Adiponectin affects nitric oxide production, and low plasma adiponectin levels are associated with impaired endothelium-dependent vasorelaxation. However, adiponectin pathophysiology in the acute phase after stroke, especially subarachnoid hemorrhage, is not well understood. The present study evaluated the changes in plasma adiponectin concentrations in patients with subarachnoid hemorrhage and investigated the relationship between plasma adiponectin and delayed cerebral ischemia. Serial plasma samples from 27 patients with subarachnoid hemorrhage were obtained on day 0 or 1 after hemorrhage, and days 3, 7, 10, 14, and 21. As a control, plasma samples were obtained from 26 healthy volunteers. Differences between patients with and without delayed cerebral ischemia were assessed to investigate the relationship between plasma adiponectin concentrations and the occurrence of delayed cerebral ischemia. There were no significant differences in the clinical characteristics of patients with and without delayed cerebral ischemia. The plasma adiponectin concentrations were significantly lower in patients on days 3 and 7 compared with controls. Plasma adiponectin concentrations in patients with delayed cerebral ischemia were significantly lower than in those without delayed cerebral ischemia on days 3, 7, 10, and 14. The present results indicate that low plasma adiponectin concentrations from day 3 to day 14 might be associated with the development of delayed cerebral ischemia.

Surgical Results After Primary Decompressive Craniectomy in Poor-Grade Aneurysmal Subarachnoid Hemorrhage

It is well known that patients with poor-grade aneurysmal subarachnoid hemorrhage (SAH) have poor outcomes owing to significant mass effect and brain stem compression. On the other hand, decompressive craniectomy (DC) has shown efficacy in reducing morbidity and mortality in patients with intracranial hypertension. Here, we study the efficacy of DC in poor-grade SAH with attention to surgical outcome. A total of 38 consecutive patients with poor-grade SAH was treated in our hospital between 1 August 2005 and 30 July 2010. Among these 38 patients, we involved 15 patients with DC in the present study. We retrospectively reviewed medical charts and radiological findings. Glasgow Outcome Scale score on discharge showed good response in 1 (6.7 %), moderate disability in 6 (40.0 %), severe disability in 4 (28.1 %), vegetative state in 2 (1.3 %), and death in 2 (13.3 %). In particular, 3 grade IV patients (50.0 %) had a favorable outcome. Recent several experimental studies also indicated that DC significantly improves outcome owing to increased perfusion pressure or reduced intracranial pressure. We suggest that the DC provided the efficacy in reducing mortality in poor-grade SAH patients.

Decrease in plasma adiponectin level and increase in adiponectin immunoreactivity in cortex and hippocampus after traumatic brain injury in rats.

AIM Adiponectin plays an important role in the regulation of tissue inflammation. Recently, it has been reported that the plasma adiponectin levels in several acute illnesses decrease periodically, thus indicating that adiponectin may play a role in the inflammatory response in patients with acute illness. However, little is known about the effects of adiponectin following TBI. The aim of the present study was to examine the changes in the plasma adiponectin levels and the immunoreactivity of adiponectin in the brain after TBI. MATERIAL AND METHODS Adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury using the Dragonfly device. Plasma adiponectin levels were determined by ELISA kit. Immunohistochemistry and Western blot analysis were performed to assess the immunoreactivity of adiponectin. RESULTS The plasma adiponectin levels gradually decreased and were significantly lower at 48 h and 72 h after injury than before injury. Immunohistochemistry and Western blot analysis showed that the adiponectin immunoreactivity was increased in the cerebral cortex at 24 hours after injury and in the hippocampus at 72 hours after injury. CONCLUSION Our findings suggest that adiponectin might participate in the pathophysiological process occurring after TBI.