Shunsuke Terasaka

Performance of Bedside Transpulmonary Thermodilution Monitoring for Goal-Directed Hemodynamic Management After Subarachnoid Hemorrhage

Background and Purpose— Early goal-directed hemodynamic therapy is of particular importance for adequate cerebral circulation of patients with vasospasm after subarachnoid hemorrhage but is often precluded by the invasiveness of established cardiac output determination using a pulmonary artery catheter. This study was undertaken to validate the usefulness of less invasive goal-directed hemodynamic monitoring by transpulmonary thermodilution technique in patients after subarachnoid hemorrhage. Methods— One hundred sixteen patients with subarachnoid hemorrhage who underwent surgical clipping within 24 hours of ictus were investigated. Validation of transpulmonary thermodilution-derived intermittent/continuous cardiac output and cardiac preload (global end diastolic volume) were compared with pulmonary artery catheter-derived reference cardiac output and pulmonary capillary wedge pressure or central venous pressure in 16 patients diagnosed with vasospasm. In a subsequent trial of 100 consecutive cases, clinical results between the new and standard management paradigms were compared. Results— Transpulmonary thermodilution-derived intermittent cardiac output and transpulmonary thermodilution-derived continuous cardiac output showed close agreement to catheter-derived reference cardiac output with high correlation (r=0.85 and 0.77) and low percentage error (13.5% and 18.0%). Fluid responsiveness to defined volume loading was predicted better with global end diastolic volume than with pulmonary capillary wedge pressure and central venous pressure for larger receiver operating characteristic curve area. Patients receiving early goal-directed management by transpulmonary thermodilution experienced reduced frequencies of vasospasm and cardiopulmonary complications compared with those managed with standard therapy (P<0.05), whereas their functional outcomes at 3 months were not different (P=0.06). Conclusions— Goal-directed hemodynamic management guided by transpulmonary thermodilution appears to have a therapeutic advantage for optimizing the prognosis of patients with subarachnoid hemorrhage with vasospasm over conventional methods.

Goal-Directed Fluid Management by Bedside Transpulmonary Hemodynamic Monitoring After Subarachnoid Hemorrhage

Background and Purpose— Optimal monitoring of cardiac output and intravascular volume is of paramount importance for good fluid management of patients with subarachnoid hemorrhage (SAH). The aim of this study was to demonstrate the feasibility of advanced hemodynamic monitoring with transpulmonary thermodilution and to provide descriptive data early after SAH. Methods— Forty-six patients with SAH treated within 24 hours of the ictus were investigated. Specific targets for cardiac index (≥3.0 L · min−1 · m−2), global end-diastolic volume index (700 to 900 mL/m2), and extravascular lung water index (≤14 mL/kg) were established by the single-indicator transpulmonary thermodilution technique, and a fluid management protocol emphasizing supplemental colloid administration was used to attain these targets. Plasma hormones related to stress and fluid regulation were also measured. Results— A higher cardiac index (mean value of 5.3 L · min−1 · m−2) and a lower global end-diastolic volume index (555 mL/m2) were observed on initial measurement, for which elevations of plasma adrenaline, noradrenaline, and cortisol were also detected. Cardiac index was progressively decreased (3.5 L · min−1 · m−2) and global end-diastolic volume index was normalized by fluid administration aimed at normovolemia. The extent of the initial hemodynamic and hormonal profile was greater in patients with a poor clinical status (P<0.05). The extravascular lung water index was mildly elevated but within the target range throughout the study period. No patients developed pulmonary edema or congestive heart failure. Conclusions— The impact of sympathetic hyperactivity after SAH predisposes patients to a hyperdynamic and hypovolemic state, especially in those whose clinical status is poor. Bedside monitoring with the transpulmonary thermodilution system may be a powerful tool for the systemic management of such patients.

Novel somatic and germline mutations in intracranial germ cell tumours

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3–4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

Sonodynamic therapy using water-dispersed TiO2-polyethylene glycol compound on glioma cells: Comparison of cytotoxic mechanism with photodynamic therapy

Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO(2)) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO(2) nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251 human glioblastoma cell lines. Water-dispersed TiO(2) nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO(2) surface (TiO(2)/PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100 μg/ml of TiO(2)/PEG for 3h and subsequently irradiated by ultraviolet light (5.0 mW/cm(2)) or 1.0MHz ultrasound (1.0 W/cm(2)). Cell survival was estimated by MTT assay 24h after irradiation. In the presence of TiO(2)/PEG, the photodynamic cytotoxic effect was not observed after 20 min of an ultraviolet light exposure, while the sonodynamic cytotoxicity effect was almost proportional to the time of sonication. In addition, photodynamic cytotoxicity of TiO(2)/PEG was almost completely inhibited by radical scavenger, while suppression of the sonodynamic cytotoxic effect was not significant. Results of various fluorescent stains showed that ultrasound-treated cells lost their viability immediately after irradiation, and cell membranes were especially damaged in comparison with ultraviolet-treated cells. These findings showed a potential application of TiO(2)/PEG to sonodynamic therapy as a new treatment of malignant gliomas and suggested that the mechanism of TiO(2)/PEG mediated sonodynamic cytotoxicity differs from that of photodynamic cytotoxicity.

Surgical Approaches for the Treatment of Aneurysms on the P2 Segment of the Posterior Cerebral Artery

OBJECTIVE The P2 segment of the posterior cerebral artery has remained a challenging region to expose surgically. We establish a surgical strategy for P2-segment aneurysms. METHODS Each segment of the posterior cerebral artery was classified according to Zeal and Rhotons classification. Fourteen of 18 P2-segment aneurysms were surgically treated. The patients outcome, the aneurysm location, and the surgical procedures were evaluated. A cadaveric study was performed to clarify the surgical view obtained via three different surgical approaches. RESULTS Nine aneurysms were clipped, two were trapped, one was coated, and one was excised with parent artery reconstruction. Cerebral revascularization techniques were used for three patients. The pterional approach exposed the anterior half of the P2a segment. The subtemporal approach revealed the P2a segment, but its exposure was restricted by its localization in the ambient cistern. Via the occipital interhemispheric transtentorial approach, the P2p segment was visible and could be manipulated. When the posterior half of P2a segment was high on a coronal view of magnetic resonance imaging, it was extremely hard to access via any approach. CONCLUSION A surgical strategy for the P2 aneurysm can be planned with accurate prediction of the aneurysm location. When the localization of an aneurysm on the posterior half of P2a segment is high, a resection of brain tissue may be required.

Evaluation of application techniques of fibrin sealant to prevent cerebrospinal fluid leakage: a new device for the application of aerosolized fibrin glue.

OBJECTIVE This report evaluates the sealing effects of fibrin sealant applied on the dura mater using different techniques. METHODS Three application methods were studied: a sequential layer method, a simultaneous method using a cannula, and a spray method using a newly developed spray device. The sealing effects of these methods were compared using in vitro histological analysis and a pressure resistance test. The clinical efficacy of the fibrin sealant to prevent water leakage through the dura mater was retrospectively analyzed in a total of 509 patients. The process of absorption of a clinically applied fibrin clot in vivo was examined using surgical specimens. RESULTS The fibrin plate made using the spray method withstood a hydrostatic pressure greater than 200 cm H2O. A scanning electron microscopic study of the fibrin clots showed that the sequential and simultaneous methods produced a fibrin fiber network; in contrast, our spray method formed a dense fibrin tissue in which the fibrin molecules fused together forming stratified laminae. Of the 295 supratentorial craniotomies during which spraying was used, postsurgical cerebrospinal fluid leakage occurred in 9 cases (3.1%), whereas of the 214 craniotomies during which spraying was not used, cerebrospinal fluid leakage occurred in 19 cases (8.9%). Histological examinations of 10 surgical specimens obtained during second craniotomies revealed that the spray-made fibrin clots had been gradually replaced by mature granulation composed of collagenous connective tissue. CONCLUSION The optimal technique for applying fibrin sealant is the spray method that aerosolizes fibrin glue and produces a tough fibrin plate.

Novel photodynamic therapy using water-dispersed TiO2-polyethylene glycol compound: evaluation of antitumor effect on glioma cells and spheroids in vitro.

Titanium dioxide (TiO2) is thought to be a photocatalytic agent excited by UV light. Our aim was to investigate the photocatalytic antitumor effect of water‐dispersed TiO2 nanoparticles on C6 rat glioma cells and to evaluate the treatment responses by the spheroid models. Water‐dispersed TiO2 nanoparticles were constructed by the adsorption of chemical modified polyethylene glycol (PEG) on the TiO2 surface (TiO2/PEG). Each monolayer and spheroid of C6 cells was coincubated with various concentrations of TiO2/PEG and subsequently irradiated with UV light. Damage of the cells and spheroids was evaluated sequentially by staining with the fluorescent dyes. The cytotoxic effect was correlated with the concentration of TiO2/PEG and the energy dose of UV irradiation. More than 90% of cells were killed after 13.5 J cm−2 of UV irradiation in the presence of 500 μg mL−1 TiO2/PEG. The irradiated spheroids in the presence of TiO2/PEG showed growth suppression compared with control groups. In TiO2/PEG‐treated spheroids, the number of Annexin V‐FITC‐stained cells gradually increased during the first 6 h, and subsequently propidium iodide‐stained cells appeared. The results of this study suggest that newly developed photoexcited TiO2/PEG have antitumoral activity. Photodynamic therapy utilizing this material can be a clue to a novel therapeutic strategy for glioma.

Does Intensive Management of Cerebral Hemodynamics and Atheromatous Aorta Reduce Stroke After Coronary Artery Surgery

BACKGROUND Atheromatous aorta and carotid artery disease are known predictors for stroke after coronary artery bypass grafting (CABG). The clinical significance of intracranial cerebral artery disease is not known. This study was designed to determine whether a therapeutic strategy based on perioperative detection of intracranial and extracranial occlusive cerebrovascular disease and atheromatous aorta could reduce perioperative stroke. METHODS We studied 485 patients who underwent isolated CABG. The control group was 247 patients who underwent standard-protocol CABG. The 238 subjects in the intervention group underwent preoperative magnetic resonance angiography of the head and neck and intraoperative epiaortic scanning. Cerebral hemodynamics were evaluated by single photon emission computed tomography and acetazolamide tests in patients with significant occlusive cerebrovascular disease. Surgical outcomes were compared. RESULTS In the intervention group, magnetic resonance angiography detected significant intracranial or extracranial occlusive cerebrovascular disease, or both, in 40 patients. Prophylactic cerebrovascular interventions were performed in 7 patients who had disturbed cerebral hemodynamics. Aorta no-touch off-pump coronary artery bypass (OPCAB) was chosen intraoperatively in 37 patients with moderate to severe atheromatous aorta. The in-hospital stroke rate was 0.42% in the intervention group vs 2.8% in the control group (p = .068). A multivariate analysis revealed that the perioperative interventional protocol was the most powerful predictor of reduced risk of perioperative stroke (odds ratio, 0.023; 95% confidence interval, 0.001 to 0.469). CONCLUSIONS Prophylactic cerebrovascular interventions and the selective use of aorta no-touch OPCAB can significantly reduce the incidence of perioperative stroke. Careful vascular evaluation before and during CABG can improve surgical outcomes.

Early Intensive Versus Minimally Invasive Approach to Postoperative Hemodynamic Management After Subarachnoid Hemorrhage

Background and Purpose— The results of previous studies suggest that early goal-directed fluid therapy (EGDT) reduces delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but the effects of EGDT on clinical outcomes are still unclear. This study aimed to determine whether EGDT improves outcomes compared with standard less-invasive hemodynamic therapy. Methods— This study included 160 patients treated within 24 hours after subarachnoid hemorrhage, randomized to receive either (1) EGDT guided by preload volume and cardiac output monitored by transpulmonary thermodilution (treatment group) or (2) standard therapy guided by fluid balance or central venous pressure, assisted by uncalibrated less-invasive cardiac output monitoring during hyperdynamic therapy in patients with clinical or radiological indications of DCI (control group). DCI determined by clinical or radiological findings and functional outcome determined by the modified Rankin Scale score at 3 months were compared between groups. Results— For all clinical grades combined, there were no significant differences in the rates of DCI (33% versus 42%; P=0.33) or modified Rankin Scale score of 0 to 3 at 3 months (67% versus 57%; P=0.22) between the 2 groups. For patients with poor clinical grade, those who received EGDT had a significantly lower rate of DCI (5% versus 14%; P=0.036), modified Rankin Scale score of 0 to 3 at 3 months (52% versus 36%; P=0.026), and shorter length of intensive care unit stay (14 versus 17 days; P=0.043) than those who received standard therapy. Conclusions— EGDT is beneficial for reducing DCI and improving postoperative functional outcome in patients with poor clinical grade. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: UMIN000007509.

Prognostic Imaging Biomarkers in Glioblastoma: Development and Independent Validation on the Basis of Multiregion and Quantitative Analysis of MR Images

PURPOSE To develop and independently validate prognostic imaging biomarkers for predicting survival in patients with glioblastoma on the basis of multiregion quantitative image analysis. MATERIALS AND METHODS This retrospective study was approved by the local institutional review board, and informed consent was waived. A total of 79 patients from two independent cohorts were included. The discovery and validation cohorts consisted of 46 and 33 patients with glioblastoma from the Cancer Imaging Archive (TCIA) and the local institution, respectively. Preoperative T1-weighted contrast material-enhanced and T2-weighted fluid-attenuation inversion recovery magnetic resonance (MR) images were analyzed. For each patient, we semiautomatically delineated the tumor and performed automated intratumor segmentation, dividing the tumor into spatially distinct subregions that demonstrate coherent intensity patterns across multiparametric MR imaging. Within each subregion and for the entire tumor, we extracted quantitative imaging features, including those that fully capture the differential contrast of multimodality MR imaging. A multivariate sparse Cox regression model was trained by using TCIA data and tested on the validation cohort. RESULTS The optimal prognostic model identified five imaging biomarkers that quantified tumor surface area and intensity distributions of the tumor and its subregions. In the validation cohort, our prognostic model achieved a concordance index of 0.67 and significant stratification of overall survival by using the log-rank test (P = .018), which outperformed conventional prognostic factors, such as age (concordance index, 0.57; P = .389) and tumor volume (concordance index, 0.59; P = .409). CONCLUSION The multiregion analysis presented here establishes a general strategy to effectively characterize intratumor heterogeneity manifested at multimodality imaging and has the potential to reveal useful prognostic imaging biomarkers in glioblastoma.