Shin-ichiro Sugiyama

Superoxide dismutase in normal cycling human ovaries: immunohistochemical localization and characterization

OBJECTIVE To investigate the expression of manganese (Mn) and copper-zinc (Cu,Zn) superoxide dismutase (SOD) in normal cycling human ovaries throughout the menstrual cycle. DESIGN Descriptive, controlled study. SETTING Tohoku University School of Medicine. PATIENT(S) Twenty-four normal cycling human ovaries were obtained from patients who underwent oophorectomy and hysterectomy for squamous cell carcinoma of the uterine cervix. INTERVENTION(S) Immunohistochemistry for Mn-SOD and Cu,Zn-SOD. MAIN OUTCOME MEASURE(S) Immunostaining. RESULT(S) In the follicular stage, Mn-SOD immunoreactivity was detected in granulosa and theca interna cells of steroid-producing follicles, that is, preantral, nondominant, dominant, and atretic follicles, whereas Cu,Zn-SOD was detected in theca interna cells of these follicles and in granulosa cells of dominant follicles. In the luteal stage, immunoreactivity for Mn-SOD and Cu,Zn-SOD was observed in both luteinized granulosa and theca cells of the functioning corpus luteum. In the early degenerating corpus luteum, both Mn-SOD and Cu,Zn-SOD were positive in steroid-producing luteinized theca cells. Mn-SOD immunoreactivity was also detected in nonsteroid-producing luteinized granulosa cells and macrophages. CONCLUSION(S) Our results suggest that the expression of Mn-SOD and Cu,Zn-SOD closely correlates with steroidogenesis in the human ovary. In addition, Mn-SOD may play an important role in the process of luteal regression.

Therapeutic efficacy of a polymeric micellar doxorubicin infused by convection-enhanced delivery against intracranial 9L brain tumor models

Convection-enhanced delivery (CED) with various drug carrier systems has recently emerged as a novel chemotherapeutic method to overcome the problems of current chemotherapies against brain tumors. Polymeric micelle systems have exhibited dramatically higher in vivo antitumor activity in systemic administration. This study investigated the effectiveness of CED with polymeric micellar doxorubicin (DOX) in a 9L syngeneic rat model. Distribution, toxicity, and efficacy of free, liposomal, and micellar DOX infused by CED were evaluated. Micellar DOX achieved much wider distribution in brain tumor tissue and surrounding normal brain tissue than free DOX. Tissue toxicity increased at higher doses, but rats treated with micellar DOX showed no abnormal neurological symptoms at any dose tested (0.1-1.0 mg/ml). Micellar DOX infused by CED resulted in prolonged median survival (36 days) compared with free DOX (19.6 days; p = 0.0173) and liposomal DOX (16.6 days; p = 0.0007) at the same dose (0.2 mg/ml). This study indicates the potential of CED with the polymeric micelle drug carrier system for the treatment of brain tumors.

Hemodynamic Analysis of Growing Intracranial Aneurysms Arising from a Posterior Inferior Cerebellar Artery

OBJECTIVE The role of hemodynamics in the growth of intracranial aneurysms is not completely clear. We present a hemodynamic study with two adjacent unruptured aneurysms arising from one parent artery but growing in different ways. This study aimed to investigate whether there were differences in hemodynamic characteristics between the two growing aneurysms. METHODS A 62-year-old female patient presented with six unruptured intracranial aneurysms. Catheter angiography at 6-month intervals revealed that two aneurysms located adjacently at the right posterior inferior cerebellar artery were growing over a 1-year period. Three-dimensional aneurysm geometries were acquired via rotational angiography. Computational fluid dynamic simulations were conducted on the 3D aneurysm geometries under patient-specific pulsatile flow conditions that were measured by magnetic resonance velocimetry. RESULTS The proximal multilobular aneurysm demonstrated high flow and physiological levels of wall shear stress (WSS) in the region of growth, whereas the distal rounded aneurysm had low flow and low WSS in the growing sac. CONCLUSION Growing aneurysms can have heterogeneous hemodynamic and morphologic characteristics and different growing patterns. Growing regions of an aneurysm could be exposed to either high WSS at the inflow zone or low WSS and high oscillatory shear in the aneurysm sac.

Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment

OBJECT Intracranial germ cell tumors (GCTs) originating in the basal ganglia are rare. The authors investigated factors related to the diagnosis of these lesions as well as outcome in order to help decrease the time to diagnosis and improve treatment efficacy. METHODS The authors reviewed the clinical features of 142 cases of intracranial GCT in their institute. Fourteen cases of basal ganglia GCT were identified. The symptoms, neuroimaging findings, delay between symptom onset and diagnosis or treatment, initial and further treatment, and outcome were investigated. RESULTS Major symptoms were motor weakness and precocious puberty. Gadolinium-enhanced T1-weighted MR images showed enhancement in 8 of 11 patients examined, but only slight hyperintensity without enhancement in 2 patients. Ipsilateral peduncle and hemispheric atrophy were found in 3 and 4 patients, respectively. Cases of basal ganglia GCT were characterized by a longer delay from the initial neuroimaging examination to diagnosis compared with GCT in other regions. Five patients had aggravated hemiparesis in the extremities due to the delay in diagnosis. Despite good response to the initial therapy, 5 patients experienced recurrence; 2 of these 5 had malignant GCTs, and 3 had been treated only with chemotherapy or radiochemotherapy with insufficient radiation dose and field. Finally, the 2 patients with malignant GCTs died of the disease, and 1 died of aspiration pneumonia due to dissemination around the brainstem. CONCLUSIONS Early diagnosis requires MR imaging with administration of contrast medium in young patients presenting with motor weakness and/or precocious puberty. Serial neuroimaging studies should be performed if any tiny lesion is detected in the basal ganglia. Since insufficient treatment resulted in early recurrence, radiation therapy with adequate dose and field is essential.

The Computational Fluid Dynamics Rupture Challenge 2013—Phase I: Prediction of Rupture Status in Intracranial Aneurysms

BACKGROUND AND PURPOSE: Rupture risk assessment for intracranial aneurysms remains challenging, and risk factors, including wall shear stress, are discussed controversially. The primary purpose of the presented challenge was to determine how consistently aneurysm rupture status and rupture site could be identified on the basis of computational fluid dynamics. MATERIALS AND METHODS: Two geometrically similar MCA aneurysms were selected, 1 ruptured, 1 unruptured. Participating computational fluid dynamics groups were blinded as to which case was ruptured. Participants were provided with digitally segmented lumen geometries and, for this phase of the challenge, were free to choose their own flow rates, blood rheologies, and so forth. Participants were asked to report which case had ruptured and the likely site of rupture. In parallel, lumen geometries were provided to a group of neurosurgeons for their predictions of rupture status and site. RESULTS: Of 26 participating computational fluid dynamics groups, 21 (81%) correctly identified the ruptured case. Although the known rupture site was associated with low and oscillatory wall shear stress, most groups identified other sites, some of which also experienced low and oscillatory shear. Of the 43 participating neurosurgeons, 39 (91%) identified the ruptured case. None correctly identified the rupture site. CONCLUSIONS: Geometric or hemodynamic considerations favor identification of rupture status; however, retrospective identification of the rupture site remains a challenge for both engineers and clinicians. A more precise understanding of the hemodynamic factors involved in aneurysm wall pathology is likely required for computational fluid dynamics to add value to current clinical decision-making regarding rupture risk.

Relative residence time prolongation in intracranial aneurysms: a possible association with atherosclerosis.

BACKGROUND Intracranial aneurysms can have atherosclerotic wall properties that may be important in predicting aneurysm history or estimating the potential risks of surgical treatments. OBJECTIVE To investigate hemodynamic characteristics of atherosclerotic lesions in intracranial aneurysms using computational fluid dynamics. METHODS Intraoperative video recordings of 30 consecutive patients with an unruptured middle cerebral artery aneurysm were examined to identify atherosclerotic lesions on an aneurysm wall. For computational fluid dynamics analyses, geometries of aneurysms and adjacent arteries were reconstructed from 3-dimensional rotational angiography. Transient simulations were conducted under patient-specific pulsatile inlet conditions measured by phase-contrast magnetic resonance velocimetry. Three hemodynamic wall parameters were calculated: time-averaged wall shear stress, oscillatory shear index, and relative residence time (RRT). Statistical analyses were performed to discriminate the risk factors of atherosclerotic lesion formation. RESULTS Among 30 aneurysms, 7 atherosclerotic lesions with remarkable yellow lipid deposition were identified in 5 aneurysms. All 7 atherosclerotic lesions spatially agreed with the area with prolonged RRT. Univariate analysis revealed that male sex (P = .03), cigarette smoking (P = .047), and maximum RRT (P = .02) are significantly related to atherosclerotic lesion on the intracranial aneurysmal wall. Of those variables that influenced atherosclerotic lesion of the intracranial aneurysmal wall, male sex (P = .005) and maximum RRT (P = .004) remained significant in the multivariate regression model. CONCLUSION The area with prolonged RRT colocalized with atherosclerotic change on the aneurysm wall. Male sex and maximum RRT were independent risk factors for atherogenesis in intracranial aneurysms.

Blood Flow Into Basilar Tip Aneurysms: A Predictor for Recanalization After Coil Embolization

Background and Purpose— Hemodynamic forces may play a role in the recanalization of coiled aneurysms. The purpose of this study was to investigate the influence of presurgical hemodynamics on the efficacy of coil embolization for basilar tip aneurysms. Methods— We identified 82 patients who underwent endovascular coil embolization for basilar tip aneurysms with a follow-up of >1 year. Presurgical hemodynamics were investigated using computational fluid dynamics with 3-dimensional data derived from rotational angiography. During postprocessing, we quantified the rate of net flow entering the aneurysm through its neck and calculated the proportion of the aneurysmal inflow rate to the basilar artery flow rate. In addition, we investigated the correlation between the basilar bifurcation configuration and the hemodynamics. Results— Twenty-five of the 82 patients were excluded because of difficult vascular geometry reconstruction. Among the 57 examined patients, angiographic recanalization was observed in 19 patients (33.3%). The proportion of the aneurysmal inflow rate to the basilar artery flow rate and a coil packing density <30% were independent and significant predictors for the recanalization of coiled aneurysms. Additional investigation revealed that a small branch angle formed by the basilar artery and the posterior cerebral artery increased blood flow into the aneurysm. Conclusions— The proportion of the aneurysmal inflow rate to the basilar artery flow rate, influenced by the basilar bifurcation configuration, was an independent and significant predictor for recanalization after coil embolization in basilar tip aneurysms.

Local convection-enhanced delivery of chemotherapeutic agent transiently opens blood–brain barrier and improves efficacy of systemic chemotherapy in intracranial xenograft tumor model

Recently, local chemotherapy proved its efficacy against malignant gliomas. Under the hypothesis that local delivery of chemotherapeutic agents into the brain parenchyma induce opening of the blood-brain barrier (BBB), we evaluated the opening of BBB after convection-enhanced delivery of nimustine hydrochloride into the brain parenchyma. Local convection-enhanced delivery of nimustine hydrochloride transiently opened the BBB from about 7-12 days after delivery in normal rodent brain. Systemic chemotherapy during this period of BBB disruption had synergistic effects resulting in prolonged survival of tumor-bearing rats. The present strategy may provide a new approach for glioma chemotherapy.

Quantitative Assessment of Circumferential Enhancement along the Wall of Cerebral Aneurysms Using MR Imaging.

BACKGROUND AND PURPOSE: The incidence of wall enhancement of cerebral aneurysms on vessel wall MR imaging has been described as higher in ruptured intracranial aneurysms than in unruptured intracranial aneurysms, but the difference in the degree of enhancement between ruptured and unruptured aneurysms is unknown. We compared the degree of enhancement between ruptured and unruptured intracranial aneurysms by using quantitative MR imaging measures. MATERIALS AND METHODS: We performed quantitative analyses of circumferential enhancement along the wall of cerebral aneurysms in 28 ruptured and 76 unruptured consecutive cases by using vessel wall MR imaging. A 3D-T1-weighted fast spin-echo sequence was obtained before and after contrast media injection, and the wall enhancement index was calculated. We then compared characteristics between ruptured and unruptured aneurysms. RESULTS: The wall enhancement index was significantly higher in ruptured than in unruptured aneurysms (1.70 ± 1.06 versus 0.89 ± 0.88, respectively; P = .0001). The receiver operating characteristic curve analysis found that the most reliable cutoff value of the wall enhancement index to differentiate ruptured from unruptured aneurysms was 0.53 (sensitivity, 0.96; specificity, 0.47). The wall enhancement index remained significant in the multivariate logistic regression analysis (P < .0001). CONCLUSIONS: Greater circumferential enhancement along the wall of cerebral aneurysms correlates with the ruptured state. A quantitative evaluation of circumferential enhancement by using vessel wall MR imaging could be useful in differentiating ruptured from unruptured intracranial aneurysms.

Safety and feasibility of convection-enhanced delivery of nimustine hydrochloride co-infused with free gadolinium for real-time monitoring in the primate brain

Abstract Objectives: Convection-enhanced delivery (CED) has been developed as an effective drug-delivery strategy for brain tumors. Ideally, direct visualization of the tissue distribution of drugs infused by CED would assure successful delivery of therapeutic agents to the brain tumor while minimizing exposure of the normal brain tissue. We previously showed the anti-tumor efficacy of nimustine hydrochloride (ACNU) delivered via CED against a rodent intracranial xenografted tumor model. Here, we developed a method to monitor the drug distribution using a non-human primate brain. Methods: CED of a mixture of ACNU with gadodiamide was performed using three non-human primates under real-time magnetic resonance imaging monitoring. Animals were clinically observed for any toxicity after infusion. Two months later, their brains were subjected to histological examination for the evaluation of local toxicity. Another one animal was euthanized immediately after CED of a mixture of ACNU, gadodiamide, and Evans blue dye to evaluate the concordance between ACNU and gadodiamide distributions. The harvested brain was cut into blocks and the ACNU content was measured. Results and discussion: Real-time magnetic resonance imaging monitoring of co-infused gadodiamide confirmed the success of the infusion maneuver. In the monkey that also received Evans blue, the distribution of Evans blue was similar to that of gadodiamide and paralleled the measured ACNU content, suggesting concordance between ACNU and gadodiamide distributions. Histological examination revealed minimum tissue damage with the infusion of ACNU at 1 mg/ml, determined as a safe dose in our previous rodent study. CED of ACNU can be co-administered with gadodiamide to ensure successful infusion and monitor the distribution volume.