Chih-Zen Chang

The conditional probabilities of survival in patients with anaplastic astrocytoma or glioblastoma multiforme

BACKGROUND By the use of conditional probabilities of survival, we studied the yearly survival rates for individual tumor survivors. METHODS Conditional survival rate was estimated in 114 consecutive patients with anaplastic astrocytoma or glioblastoma multiforme. Conditional probabilities of surviving some years given survival to a specific period of time after craniotomy and 95% confidence intervals were calculated in the individual tumor survivors. RESULTS The estimated median survival was 30 months for 45 patients with anaplastic astrocytoma and 12 months for 69 patients with glioblastoma multiforme. The conditional probabilities of surviving next one year given survival to 1 year, 2 years, 3 years, 4 years, or 5 years after craniotomy for anaplastic astrocytoma were 86.2%, 75.0%, 85.9%, 77.8%, or 85.7%, respectively; for glioblastoma multiforme 64.8%, 58.7%, 85.7%, 80.0%, or 75.0%, respectively. The conditional probability of surviving to 5 years given survival to 2 years after craniotomy for anaplastic astrocytoma, i.e., surviving an additional 3 years, was 50.1%, which was better than observed 5-year survival rate (28.6%); for glioblastoma multiforme it was 40.2%, which also was better than observed 5-year survival rate (12.4%). CONCLUSIONS The conditional probability of survival was a good method to clinically predict yearly survival rate for individual tumor survivors. In addition, the method can estimate the probabilities of surviving next some years given survival to a specific period of time after craniotomy. It also showed a more encouraging result than observed survival rate in patients with supratentorial malignant astrocytomas.

Factors influencing seizures in adult patients with supratentorial astrocytic tumors

SummarySeizures and epilepsy in adults are important and increasingly common clinical problems. Despite this, the investigation of seizures in adults with astrocytic tumors remains a grey area. The incidence and influencing factors of preoperative and postoperative seizures were evaluated in 101 patients of 45 years or older with supratentorial astrocytic tumors. Preoperative seizures occurred in 14 (14%) patients. Seizures at presentation were significantly correlated with pathological grades of astrocytic tumors (p=0.0318). The risk of seizures at presentation was greatest in patients with well-differentiated astrocytomas as compared with anaplastic astrocytomas (Odds ratio=4.364, p=0.056) or glioblastomas multiforme (Odds ratio=5.673, p=0.007). There was no association of preoperative seizures with age, sex, location or site of the tumors. Postoperative seizures occurred in 18 (18%) patients, including 8 (8/14, 57%) recurrent seizures and 10 (10/87, 12%) late-onset seizures. Postoperative seizures were significantly correlated with the presence of preoperative seizures (p=0.0003). The presence of preoperative seizures was potentially predictive of postoperative seizures when evaluated by logistic regression model (Odds ratio=6.650). Thirteen (72%) of 18 patients with postoperative seizures were associated with tumor recurrence in 7 cases, hemorrhage in 3 cases and malignant progression in 3 cases. There was no association of postoperative seizures with age, sex, location or site of the tumors, grades of tumors, type of preoperative seizures, duration of preoperative seizures, serum level of anticonvulsant drug, extent of surgery, postoperative radiation or chemotherapy. The patients with preoperative seizures had a higher risk of postoperative seizures and should be carefully monitored. Imaging examination of brain to exclude the possibilities of tumor recurrence or hemorrhage is warrantable in supratentorial astrocytoma patients with postoperative seizures.

Preoperative and postoperative seizures in patients with astrocytic tumours: analysis of incidence and influencing factors ☆

To evaluate the incidence and influencing factors related to preoperative and postoperative seizures, a retrospective analysis was performed in 190 patients with astrocytic tumours. Preoperative seizures occurred in 50 (26%) patients and 27 (54%) of the m had recurrent seizures. Late-onset seizures developed after craniotomy in 11 (8%) of 140 patients. Seizures at presentation were significantly correlated with age at diagnosis (P=0.0204) and pathological grade of tumour (P=0.0040). The patients aged less than 40 years had a high risk of seizures at presentation (odds ratio=3.076, P=0.0134). Postoperative seizures were significantly associated with the presence of preoperative seizures (P<0.0001), type or duration of preoperative seizures (P<0.0001, P<0.0001, respectively) and serum level of anticonvulsant drug (P=0.0068). However, only the presence of preoperative seizures had a potential for prediction of postoperative seizures when evaluated by logistic regression model (odds ratio=20.859, P=0.0001). Fifty-nine percent of patients with recurrent seizures and 64% of patients with late-onset seizures had seizures which occurred within 6 months after craniotomy. Despite therapeutic anticonvulsant levels, most postoperative seizures were associated with tumour recurrence or haemorrhage. Postoperative seizures commonly occurred relatively soon after craniotomy and prophylactic anticonvulsants should be given. In patients with postoperative seizures, particularly in the presence of therapeutic anticonvulsant level, brain computed tomography should be performed to exclude tumour recurrence or haemorrhage.

Continuous Intravenous Infusion of CGS 26303, an Endothelin-converting Enzyme Inhibitor, Prevents and Reverses Cerebral Vasospasm after Experimental Subarachnoid Hemorrhage

OBJECTIVEEndothelin-mediated vasoconstriction has been implicated in the pathophysiology of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Endothelin-1, the most potent vasoconstrictor peptide of the endothelin family, is synthesized initially as a large prepropeptide that requires multiple steps of post-translational processing for activation. The final step of this processing involves the proteolytic cleavage of a relatively inactive precursor, big endothelin-1, by the metalloprotease endothelin-converting enzyme. Previous findings have demonstrated that intravenous bolus injections of an endothelin-converting enzyme inhibitor (CGS 26303) administered twice daily can prevent and reverse arterial narrowing in a rabbit model of SAH. However, attenuation of vasospastic response was incomplete and required relatively high doses to be effective in reversing vasospasm. Therefore, the present study evaluated an alternative protocol for administration of CGS 26303 to optimize the antispastic influence of this compound. METHODSContinuous intravenous infusion of CGS 26303 at doses of 2.4, 8.0, or 24.0 mg/kg/d was initiated either 1 hour (prevention paradigm) or 24 hours (reversal paradigm) after experimental SAH in New Zealand White rabbits. All animals were killed by perfusion-fixation 48 hours after SAH. Basilar arteries were then removed and sectioned, and their cross-sectional areas were measured by use of computer-assisted video microscopy. RESULTSContinuous intravenous infusion of CGS 26303 attenuated SAH-induced cerebral vasospasm in a dose-dependent manner in both the prevention and the reversal groups. These effects achieved statistical significance at all doses as compared with the SAH-only or SAH-plus-vehicle groups. Furthermore, the attenuation of vasospasm after continuous infusion of CGS 26303 was more efficacious than that obtained with bolus injections. CONCLUSIONThese findings provide further support for the use of endothelin-converting enzyme inhibition as a therapeutic strategy for reduction of cerebral vasospasm, and they also support the effectiveness of this strategy even when initiated after arterial narrowing has been established. The findings also indicate that continuous intravenous infusion of CGS 26303 is a more effective approach for attenuation of vasospasm than bolus intravenous administration.

Attenuation of SAH-induced cerebral vasospasm by a selective ECE inhibitor

CGS 26303, a dual inhibitor of endothelin-converting enzyme-1 (ECE-1) and neutral endopeptidase 24.11, was previously shown to prevent and reverse vasospasm in an experimental model of subarachnoid hemorrhage (SAH). However, reversal of the vasospastic response was not very efficacious. This study was designed to examine the effects of a highly selective ECE-1 inhibitor, CGS 35066, on SAH-induced cerbrovasospasm. Experimental SAH was induced in New Zealand white rabbits by injecting autogenous blood into cisterna magna and CGS 35066 was injected i.v. twice daily, either at 1 h (prevention protocol) or 24 h (reversal protocol) after SAH. Treatment with CGS 35066 significantly attenuated basilar arterial narrowing at a dose of 1 mg/kg in both protocols. These findings provide support for the use of selective ECE-1 inhibitors for the treatment of SAH-induced vasospasm even after the process of arterial narrowing has begun.

Curcumin, encapsulated in nano-sized PLGA, down-regulates nuclear factor κB (p65) and subarachnoid hemorrhage induced early brain injury in a rat model

BACKGROUND More and more evidence revealed early brain injury (EBI) may determine the final outcome in aneurismal subarachnoid hemorrhage (SAH) patients. This study is of interest to examine the efficacy of nano-particle curcumin (nanocurcumin), a diarylheptanoid, on a SAH-induced EBI model. METHODS A rodent double hemorrhage model was employed. Nanocurcumin (75/150/300μg/kg/day) was administered via osmotic mini-pump post-SAH. CSF samples were collected to examine IL-1β, IL-6, IL-8 and TNF-α (rt-PCR). Cerebral cortex was harvested for NF-κB (p50/p65) (western blot), caspases (rt-PCR) measurement. RESULTS Nanocurcumin significantly reduced the bio-expression of NF-κB (p65), when compared with the SAH groups. The levels of IL-1β and IL-6 were increased in animals subjected to SAH, compared with the healthy controls, but absent in the high dose nanocurcumin+SAH group. Moreover, the levels of TNF-α in the SAH groups were significantly elevated. Treatment with nanocurcumin (300μg/kg) reduced the level to the healthy control. The cleaved caspase-3 and -9a was significantly reduced in 300μg/kg nanocurcumin treatment groups (P<0.05). CONCLUSION Treatment with nanocurcumin exerts its neuroprotective effect through the upward regulation of NF-κB (p65) and also reduced mitochondrion related caspase-9a expression. Besides, nanocurcumin decreased CSF levels of TNF-α and IL-1β, which may contribute to the extrinsic antiapoptotic effect. This study shows promise to support curcuminin, in a nano-particle, could attenuate SAH induced EBI.

Attenuation of hemolysate-induced cerebrovascular endothelial cell injury and of production of endothelin-1 and big endothelin-1 by an endothelin-converting enzyme inhibitor

BACKGROUND Endothelin-1 (ET-1) is a potent and long-acting vasoconstrictive peptide that has been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). ET-1 has been shown to be present in the cerebrospinal fluid of patients after SAH, and substances produced during hemolysis of subarachnoid blood clots are believed to be responsible for stimulating the production of ET-1. The biosynthesis of ET-1 is a multi-step process, involving the conversion of the relatively inactive precursor big ET-1 to the mature peptide by endothelin converting enzyme (ECE), a metalloprotease. Consequently, ECE inhibitors are expected to suppress the biosynthesis of ET-1 and reduce the pathologic impact resulting from overproduction of this peptide. The purpose of the present study was to investigate the effects of an ECE inhibitor, CGS 26303, on hemolysate-induced injury of cerebral vessel endothelial cells as well as the production of ET-1 from these cells. METHODS Different doses of CGS 26303 and hemolysate were added to the culture medium for 48 hours. Cell injury was assessed by cell morphology and density, while the productions of ET-1 and big ET-1 were determined by radioimmunoassays. RESULTS Hemolysate alone increased the levels of ET-1 and big ET-1 in culture medium and caused substantial cell loss. Treatment with CGS 26303 inhibited the hemolysate-induced increases in the levels of ET-1 and big ET-1 and reduced endothelial cell injury. The protective effects of CGS 26303 were modest when this inhibitor was added simultaneously with hemolysate, but were prominent and dose-dependent when the inhibitor was given 30 minutes before the addition of hemolysate. CONCLUSION These results suggest that overproduction of ET-1 contributes significantly to hemolysate-induced damage to cerebrovascular endothelial cells.

Progesterone attenuates experimental subarachnoid hemorrhage-induced vasospasm by upregulation of endothelial nitric oxide synthase via Akt signaling pathway.

Cerebral vasospasm is the leading cause of mortality and morbidity in patients after aneurysmal subarachnoid hemorrhage (SAH). However, the mechanism and adequate treatment of vasospasm are still elusive. In the present study, we evaluate the effect and possible mechanism of progesterone on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH. Progesterone (8 mg/kg) was subcutaneously injected in ovariectomized female Sprague-Dawley rats one hour after SAH induction. The degree of vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and phosphorylated Akt (phospho-Akt) in basilar arteries were evaluated. Prior to perfusion fixation, there were no significant differences among the control and treated groups in physiological parameters recorded. Progesterone treatment significantly (P < 0.01) attenuated SAH-induced vasospasm. The SAH-induced suppression of eNOS protein and phospho-Akt were relieved by progesterone treatment. This result further confirmed that progesterone is effective in preventing SAH-induced vasospasm. The beneficial effect of progesterone might be in part related to upregulation of expression of eNOS via Akt signaling pathway after SAH. Progesterone holds therapeutic promise in the treatment of cerebral vasospasm following SAH.

Oral administration of an inhibitor of endothelin-converting enzyme attenuates cerebral vasospasm following experimental subarachnoid haemorrhage in rabbits.

Increasing evidence has implicated endothelin-1 (ET-1), a potent vasoconstrictive peptide, in the pathophysiology of cerebral vasospasm after subarachnoid haemorrhage (SAH). Endothelin-converting enzyme-1 (ECE-1), the protease involved in the final step of post-translational processing of ET-1, cleaves the inactive precursor big ET-1 at the Trp(21)-Val (22) peptide bond. In our previous study, we found that an inhibitor of ECE-1, CGS 26303, could prevent and reverse the arterial narrowing after SAH in rabbits. CGS 26393, a prodrug of CGS 26303, is an orally active, long-acting inhibitor of ECE-1. The present study examined the effects of CGS 26393 on the prevention and reversal of cerebral vasospasm after SAH. New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. In the prevention study, the drug was given orally 1 h before the induction of SAH. All drug treatments in the reversal study were initiated at 23 h after induction of SAH. One of three dosages (3, 10 or 30 mg/kg) of CGS 26393 or vehicle was administrated orally twice daily, and all animals were sacrificed by perfusion and fixation 48 h after SAH. Basilar arteries were removed and sectioned, and cross-sectional areas were measured. Cerebrospinal fluid (CSF) was collected prior to perfusion. Oral administration of CGS 26393 attenuated SAH-induced cerebral vasospasm in a dose-dependent manner in both the prevention and reversal groups. These effects achieved statistical significance at all dosages when compared with the SAH-only or SAH plus vehicle groups. Moreover, the attenuation of vasospasm following oral administration of CGS 26393 was more efficacious than that obtained with bolus injections of CGS 26303. The levels of free CGS 26303 in the CSF were increased in a dose-dependent manner in all three CGS 26393-treated groups. This study provides the first evidence that oral administration of an inhibitor of ECE-1, CGS 26393, is capable of preventing and reversing cerebral vasospasm following SAH. These findings also reinforce evidence demonstrating that treatment with an ECE-1 inhibitor is a potentially viable therapeutic approach for reducing cerebral vasospasm after SAH.

17β-Estradiol attenuates secondary injury through activation of Akt signaling via estrogen receptor alpha in rat brain following subarachnoid hemorrhage

BACKGROUND Apoptosis is implicated in vasospasm and the long-term sequelae of subarachnoid hemorrhage (SAH). This study tested the hypothesis that attenuation of SAH-induced apoptosis after 17β-estradiol (E2) treatment is associated with an increase in phosphorylation of Akt via estrogen receptor-α (ER-α) in rats. MATERIALS AND METHODS We examined the expression of phospho-Akt, ERα and ERβ, and apoptosis in cerebral cortex, hippocampus, and dentate gyrus in a two-hemorrhage SAH model in rats. We subcutaneously implanted other rats with a silicone rubber tube containing E2; they received daily injections of nonselective estrogen receptor antagonist (ICI 182,780), selective ERα-selective antagonist (methyl-piperidino-pyrazole), or ERβ-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. RESULTS At 7 d after the first SAH, protein levels of phospho-Akt and ERα were significantly decreased and caspase-3 was significantly increased in the dentate gyrus. The cell death assay revealed that DNA fragmentation was significantly increased in the dentate gyrus. Those actions were reversed by E2 and blocked by ICI 182,780 and methyl-piperidino-pyrazole, but not R,R-tetrahydrochrysene. However, there were no significant changes in the expression of the protein levels of phospho-Akt, ERα, ERβ, and caspase-3, and DNA fragmentation after SAH. CONCLUSIONS The present study shows that a beneficial effect of E2 in attenuating SAH-induced apoptosis is associated with activation of the expression of phospho-Akt and ERα, and alteration in caspase-3 protein expression via an ERα-dependent mechanism in the dentate gyrus. These data support further the investigation of E2 in the treatment of SAH in humans.