GDC-0032 inhibits cell viability and induces DNA damage in U251 human glioma cells / 中国病理生理杂志

AIM:To investigate the effect of phosphatidylinostiol 3-kinase ( PI3K) inhibitor GDC-0032 on cell viability, cell cycle and DNA damage in human glioma U 251 cells.METHODS:The cell viability was analyzed by MTT assay.The cell cycle distribution of U251 cells was examined by flow cytometry .The protein expression was examined by Western blot.The expression and localization of γ-H2AX were determined by laser-scanning confocal microscopy .RE-SULTS:GDC-0032 inhibited the cell viability in a dose-dependent manner .U251 cells showed G 1 phase arrest accompa-nied with upregulation of p 27 protein after exposure to GDC-0032, while the expression of cell division cycle protein 2 (Cdc2) was inhibited.GDC-0032 treatment increased the formation of γ-H2AX foci and histone H2AX phosphorylation in the U251 cells.In addition, GDC-0032 upregulated the phosphorylation levels of mitogen-activated protein kinases , inclu-ding extracellular signal-regulated kinase ( ERK) and c-Jun N-terminal kinase ( JNK) , in the glioma cells , while the ex-pression of survivin was inhibited .CONCLUSION:GDC-0032 inhibits U251 cell growth by inhibition of cell viability and cell cycle progression.GDC-0032 also induces DNA damage of U251 cells.The anticancer activity of GDC-0032 is associ-ated with increasing the activity of ERK and JNK and downregulating the expression of survivin .

GDC-0032 inhibits cell viability and induces DNA damage in U251 human glioma cells / 中国病理生理杂志

AIM:To investigate the effect of phosphatidylinostiol 3-kinase ( PI3K) inhibitor GDC-0032 on cell viability, cell cycle and DNA damage in human glioma U 251 cells.METHODS:The cell viability was analyzed by MTT assay.The cell cycle distribution of U251 cells was examined by flow cytometry .The protein expression was examined by Western blot.The expression and localization of γ-H2AX were determined by laser-scanning confocal microscopy .RE-SULTS:GDC-0032 inhibited the cell viability in a dose-dependent manner .U251 cells showed G 1 phase arrest accompa-nied with upregulation of p 27 protein after exposure to GDC-0032, while the expression of cell division cycle protein 2 (Cdc2) was inhibited.GDC-0032 treatment increased the formation of γ-H2AX foci and histone H2AX phosphorylation in the U251 cells.In addition, GDC-0032 upregulated the phosphorylation levels of mitogen-activated protein kinases , inclu-ding extracellular signal-regulated kinase ( ERK) and c-Jun N-terminal kinase ( JNK) , in the glioma cells , while the ex-pression of survivin was inhibited .CONCLUSION:GDC-0032 inhibits U251 cell growth by inhibition of cell viability and cell cycle progression.GDC-0032 also induces DNA damage of U251 cells.The anticancer activity of GDC-0032 is associ-ated with increasing the activity of ERK and JNK and downregulating the expression of survivin .

Validation of a method for the determination of thiocyanate in human plasma by UV/VIS spectrophotometry and application to a Phase I clinical trial of GDC-0425

The development and validation of a method for the determination of concentrations of thiocyanate in human plasma are described here. A modified colorimetric method of Bowler was used with the following alteration in Monica Manual, Part III. In order to obtain the same sensitivity in low amounts of clinical samples, quartz SUPRASIL(R) micro cuvettes have been used. The quantitation range was between 25-500 microM. Accuracy and precision of the quality control samples, linearity of the calibration curve, dilution, spike recovery and stability under various conditions were evaluated in the validation of the method and all demonstrated acceptable results. All validation results met good laboratory practice acceptance and FDA requirements to be acceptable for application in clinical trials. The validated method has been used for a Phase I clinical study in cancer patients orally administered with either 60 mg or 80 mg of GDC-0425 containing a cyanide (CN-) group. The thiocyanate levels from patients before and after drug administration showed no clinically significant differences.

Retroperitoneal hematoma after coil embolization of cerebral aneurysm: A case report / 대한마취과학회지

We present the case of a 57-year-old man who developed retroperitoneal hemorrhage due to unintentional arterial puncture during femoral artery cannulation for Guglielmi detachable coil embolization. On emergence from anesthesia, he developed severe hypotension. Computed tomographic angiogram of the abdomen showed retroperitoneal hematomas around the urinary bladder, liver, and spleen. Because femoral artery cannulation is a common procedure for intravascular embolization in neuroradiologic procedures, Clinicians should be aware of the development of severe hematomas as a consequence of femoral artery puncture.

The application of "Basket" skill in the interventional therapy for intracranial aneurysm / 中国综合临床

Objective To study the ways,mechanism,indication,curative effect of " Basket" skill applied in the interventional therapy for intracranial aneurysm. Methods Intracranial aneurysm with 1 : 1 ≥ neck/body ≥ 1 : 2 ," 3 D coil" was used to form a basket in it;in that with 1:2 > neck/body,common "2D coil" was applied. And the following coils were applied with hydrocoil or fibered coil combined with common platinum coil to increase the embol-ism density. Results In 156 cases with 158 aneurysms,143 aneurysms were 100% embolized (90. 5% ) ;131 ca-ses discharged with GOS 5 score(84.0% ),and 2 cases died ( 1.3% ). Conclusion " Basket" skill can increase the embolization density in aneurysm,reducing the residual of the neck,getting embolizated fully and improving the prognosis.

Multi-Modality Treatment for Intracranial Arteriovenous Malformation Associated with Arterial Aneurysm

OBJECTIVE: Intracranial arteriovenous malformation (AVM) associated with aneurysm has been infrequently encountered and the treatment for this malady is challenging. We report here on our clinical experience with AVMs associated with arterial aneurysms that were managed by multimodality treatments, including clipping of the aneurysm, microsurgery, Gamma-knife radiosurgery (GKS) and Guglielmi detachable coil (GDC) embolization. METHODS: We reviewed the treatment plans, radiological findings and clinical courses of 21 patients who were treated with GKS for AVM associated with aneurysm. RESULTS: Twenty-seven aneurysms in 21 patients with AVMs were enrolled in this study. Hemorrhage was the most frequent presenting symptom (17 patients : 80.9%). Bleeding was caused by an AVM nidus in 11 cases, aneurysm rupture in 5 and an undetermined origin in 1. Five patients were treated for associated aneurysm with clipping followed by GKS for the AVM and 11 patients were treated with GDC embolization combined with GKS for an AVM. Although 11 associated aneurysms remained untreated after GKS, none of them ruptured and 4 aneurysms regressed during the follow up period. Two aneurysms increased in size despite the disappearance of the AVM nidus after GKS and then these aneurysms were treated with GDC embolization. CONCLUSION: If combined treatment using microsurgery, GKS and endovascular treatment can be adequately used for these patients, a better prognosis can be obtained. In particular, GKS and GDC embolization are considered to have significant roles to minimize neurologic injury.

Acute cerebral infarction due to thrombus formation during GDC embolization for the treatment of intracranial aneurysm: A case report / 대한마취과학회지

Although Guglielmi Detachable Coil (GDC) endovascular treatment of intracranial aneurysms has become an alternative to surgery, the main complication continues to be thromboembolic events. In our patient, we found thrombus at the third branch of the right middle cerebral artery after coil embolization. We added intravenous heparin and gave abciximab, an antiplatelet agent through the catheter. We then elevated the blood pressure and administered intravenous colloid solution to maintain adequate collateral circulation. One day later, the patient presented with acute focal infartion in the right frontal lobe and we treated her with low molecular weight heparin. After seven days, the patient's symptoms disappeared, and there was no residual neurological deficit. Therefore, we believe potential clinical complications can be avoided through early recognition of thrombus and appropriate medical therapy. Furthermore, it is necessary to prevent hypotension and to maintain proper hematocrit levels during operations in patients having risk factors for thrombosis.

Results of Surgical and Endovascular Treatment of Middle Cerebral Artery Bifurcation Aneurysms: Clinical Research / 대한뇌혈관외과학회지

OBJECTIVE: Endovascular treatment as well as surgical treatment has become a treatment method for the management of the intracerebral aneurysms. The authors present the results of surgical and endovascular treatment of middle cerebral artery (MCA) bifurcation aneurysms. METHODS: From 1999 to 2005, 54 MCA bifurcation aneurysms were treated with surgical or endovascular methods at our hospital. Forty two patients had ruptured aneurysms and 12 had unruptured aneurysms. Of 54 aneurysms, 33 were treated with surgical clipping, 20 with Guglielmi detachable coil (GDC) embolization and 1 with cross over treatment. The medical, radiological and operation records were reviewed retrospectively. RESULTS: Of the 54 patients, 37 (68.5%) were female and 17 (31.5%) were male. In the surgically treated group, 22 (66.7%) experienced excellent or good outcomes (GOS 5 or 4), 8 (24.2%) had fair or poor outcomes (GOS 2 to 3), and 3 (9.1%) died (GOS 1). In the endovascularly treated group, 15 (75%) had excellent or good outcomes, 1 (5.0%) had fair outcomes (GOS 3), and 4 (20%) died. Symptomatic vasospasm revealed 9 (25.7%) in the surgically treated group, and 6 (30%) in the endovascularly treated group. Seven (20.5%) complications occurred from the surgical group, 3 (15%) from the endovascular group. On logistic regression analysis, there were no significant differences in GOS and vasospasm between surgically treated group and endovascularly treated group (p=0.788, 0.643, respectively). CONCLUSION: Endovascular treatment of MCA bifurcation aneurysms results in clinical outcome equal to the outcome of surgical treatment of MCA bifurcation aneurysms and it can be a good alternative method for MCA bifurcation aneurysms treatment.

Angiographic follow-up of cerebral aneurysms treated with Guglielmi detachable coils(GDCs): An analysis of 162 cases of 173 aneurysms / 介入放射学杂志

Objective To evaluate the mid- and long-term radiological outcomes of cerebral aneurysms with GDCs embolization.Methods One hundred and sixty-two patients with 173 aneurysms embolized with GDCs underwent angiographic follow-up from 1 to 54 months post-operatively and were retrospectively reviewed. Three neuro-radiologists reviewed each angiogram and made a comparison between initial and follow-up angiograms. Morphological outcomes were evaluated as follows: unchanged; progressive thrombosis; and re-opening or re-growth. Results Of 173 aneurysms with GDC embolization, 142 aneutysms had total or nearly total occlusion, 23 subtotal occlusion and 8 partial occlusion shown on initial angiograms. The incidence of re-opening was 17.1% (13/76) in less than 3 months, and 6.2% (6/97) between 3 and 6 months postoperatively. Four aneurysms showed recurrency(2.3%) on second follow-up angiography in one year after procedure and one-year cumulative recurrent rate was 13.3% of 56 aneurysms with the third follow-up angiography in the post-operation period of 12 to 54 months, four showed a little enlargement and the cmnulative recurrent rate so far was 20.2% (35/173). Conclusions The direct and main causes for aneurysmal recurrence are incomplete and loosening packing. The first angiographic follow-up is recommended to be performed at 3 months or earlier after the procedure, especially in aneurysms with initial incomplete occlusion. Re-treatment with balloon- or stent-assisted coil embolization is recommended in re-opening aneurysms. (J Intervent Radiol,2005,14:472-479)

The Analysis of Procedural Complications of Endovascular Aneurysm Coiling with GDC

OBJECTIVE: The safety and effectiveness of Guglielmi Detachable Coil(GDC) embolization for cerebral aneurysm has been well documented. However, domestically there are few reports. The purpose of this study is to analyze procedural complications that occurred during endovascular coilling performed for cerebral aneurysms retrospectively. METHODS: From January 1996 to December 2003, a total of 453 patients (484 aneurysms) who had undergone GDC embolization for cerebral aneurysm were selected. The aneurysms were classified according to rupture history, location, dome and neck size. Procedural complications such as aneurysmal rupture, thrombosis and occlusion of patent vessels due to coil escape were noted. RESULTS: Procedural complications occurred 49 cases (10.1%). Among these, there were 27 of procedure-related aneurysmal rupture (5.6%), 14 of thrombosis (2.9%), 8 of occlusion of patent vessels due to coil escape (1.7%). Death or severe neurological deficit were seen in 18 cases of procedure-related rupture, 9 cases of thrombosis and 4 cases of coil escape. Procedure-related mortality and morbidity rates for endovascular coiling were calculated to be 2.9% and 3.6% respectively. CONCLUSION: The potential complications associated with shape, size and relationship to parent vessels of each specific cerebral aneurysm must be considered carefully before treatment. In order to reduce complications, proper equipment, knowledge on the hemodynamics and vascular anatomy, and operator's expertise are desired.

Therapeutic Results of Dissecting Aneurysms of Vertebral Artery

OBJECTIVE: We present a retrospective analysis of clinical characteristics of vertebral artery dissecting aneurysms and efficacy of treatment outcome according to the various treatment modalities. METHODS: From March 2001 to February 2002, seven patients with dissecting aneurysm of vertebral artery were diagnosed by cerebral angiography. Five patients presented with subarchnoid hemorrhage and two patients with mass effect. Five patients were treated endovascularly using Guglielmi detachable coils and a patient with severe brainstem compression underwent direct surgery. Another patient rebled before treatment and subsequently died. RESULTS: We had no endovascular procedure-related complications. Four patients with subarachnoid hemorrhage who underwent endovascular treatment survived with good recovery. One of them rebled after initial treatment and was treated by additional endovascular procedure. Among patients with mass effect, one patient was treated with proximal occlusion of vertebral artery and another underwent complete excision of aneurysm, with anastomosis of the PICA into the dissecting aneurysm proximal portion. We obtained a good treatment results with improvement of myelopathy in both patients, however, the patients who had underwent bypass surgery suffered from transient lower cranial nerve palsy. CONCLUSION: The endovascular treatment for vertebral artery dissecting aneurysm could be the treatment of choice for these lesions to prevent early rebleeding and obtain optimal results. However, the choice for the treatment modality in such lesions should be determined according to the individual lesions considering the status of patients, clinical characteristics, and relation with posterior inferior cerebellar artery.

Cerebral Vasospasm after Surgical Clipping Versus GDC Embolization in Ruptured Intracranial Aneurysm

OBJECTIVE: The purpose of this study is to analyze the influence of the treatment modality(surgical cilpping versus GDC embolization) on development of cerebral vasospasm in a non-randomized retrospective analysis of 93 patients of aneurysmal subarachnoid hemorrhage. METHODS: The following parameters were retrospectively reviewed in our institution's data base and analyzed in association with vasospasm-related ischemic infarctions: 1) Hunt and Hess(H&H) grade, 2) Fisher group, 3) location of aneurysm, 4) treatment modality(surgical cilpping versus endovascular treatment). RESULTS: Of the 93 patients, 39 (41.9%) patients suffered delayed ischemic infarctions. The incidence of delayed ischemic infarctions were increased as higher H&H grade and Fisher group but was not related with the location of aneurysms and the treatment modalities. CONCLUSION: Even with vigorous removal of the subarachnoid blood clots in the surgical clipping group, there is no statistical differences in the incidence of cerebral vasospasm between the two treatment modalities.

Guglielmi Detachable Coil Embolization of Incompletely Surgically Clipped Anterior Communicating Artery Aneurysm: Case Report

Residual intracranial aneurysm represents a continued risk of rupture and hemorrhage after incompletely surgically aneurysmal clipping. The authors describe a case of residual anterior communicating artery aneurysm after incomplete clipping, which was successfully managed by Guglielmi detachable coil(GDC) embolization. The endovascular treatment using GDC may be a good therapy for those patients in whom microsurgical clipping results in incomplete occlusion of the aneurysm and in whom reoperation is considered contraindicated or is unacceptable to patients.

Experience of Endovascular Treatment of Distal Posterior Cerebral Artery Aneurysms

OBJECTIVE: Distal posterior cerebral artery(PCA) aneurysms requiring the problematic surgical approaches are rarely encountered. With the development of endovascular treatment, distal PCA aneurysms tend to be treated by endovascular method rather than surgery. We report our experience of distal PCA aneurysms, which were managed mainly by endovascular treatment. METHODS: During the last 5 years, there were five patients harboring distal PCA aneurysms(0.7% among a total 656 intracranial aneurysms). Four patients presented with subarachnoid hemorrhage, while one presented with ipsilateral facial hypesthesia. Four of them were treated by endovascular(Guglielmi detachable coil: GDC) embolization and one was treated by surgical clipping after failure of GDC embolization. RESULTS: Complete obliteration with parent artery encroachment was confirmed in 2 cases. There was one occipital lobe infarction and it resulted in the homonymous quadrantanopsia. In the other case, cerebral infarction did not develop. Incomplete coil embolization was inevitably performed to avoid parent artery occlusion in another two cases. CONCLUSION: Even with the obliteration of the parent artery, distal PCA aneurysms could be treated by use of GDC effectively. Adequate collateral supply to the distal arterial territory seems to contribute to it. Further study needs to be performed to verify this hypothesis.

Value of stent placement in treatment of fusiform aneurysms and dissecting aneurysm of vertebral artery / 介入放射学杂志

Objective To summarize the technique of stent placement in treatment of fusiform aneurysms and dissecting aneurysms of vertebral artery. Methods we report a retrospective analysis of 16 aneurysms which underwent stent placement ,9 fusiform aneurysms which performed by using stent and GDC;7 dissecting aneurysms which performed by using stent first, Stent placement was followed by coil placement in the 5 aneurysms. Results all patients were cured,2 of 11 aneurysm showed up transient ischemia of cerebral.Follow-up angiographic studies performed in 13 patients from 3 months to 24 months revealed no aneurysm regrowth and no incident of in-stent stenosis.Conclusions the treatment of fusiform aneurysms and dissecting aneurysm of vertebral artery is distinguishing, Using stent combined with GDC to treat fusiform and dissecting aneurysm may restore the patency of parent artery and become safe and effective treatment for fusiform and dissecting aneurysm of vertebral artery.

Application of Guglielmi Detachable Coil Emboliza tion in Treatment of Intracranial Aneurysms / 介入放射学杂志

Objective To To evaluate the efficacy of Guglielmidetachable coil (GDC)F embolization in treatment of intracranial aneurysms and summarize the main points of GDC manipulation.Methods Thirty two patients were examined with digital substraction angiography (DSA) and 34 intracranial aneurysms were found, including 15 aneurysms in the anterior communication artery, 13 in the posterior communi cation artery, 2 in the middle cerebral a rtery, 1 in the anterior cerebral artery and 1 Ophthalmic artery. After wards GDC was used for embolization therapy. Results Thirty two patients with 34 aneurysms were successfully embolized with GDCs. Complete embolization achieved in 20 patients and incomplete in 12 patients; while one aneurysm ruptured during the performance, but all curedafter treatment. Vas cular spasm occurred in 2 patients, one of them had slight hemiplegia. Sixpatients with 7 aneurysms were followed up by DSA examinationl year after operation. No obvious change was observed.Conclusions Treatment of intracranial aneurysms with GDC embolization is a safe, reliable, and effective measure. Skillful techniques of the operator and correct management of complications are important factors affecting the outcome of operation. A period follow up is essential to patients with partial embolism.

Radiation Dermatitis after GDC Embolization: Case Report

Guglielmi Detachable Coil(GDC) embolization is interventional radiology procedure for the management of aneurysm. The technique is recommended in case of patients' poor general condition, difficult surgical approach, but there is concerning about complications due to radiation exposure. We experienced a patient of radiation-induced dermatitis after GDC embolization. She presented with erythema, pus-like discharge, ulceration on scalp and right preauricular area, which symptoms was improved with medical managements. The authors report the case with pertinent literature review.

The Quality of Life and Cognitive Deficits According to Treatment Modality of Anterior Communicating Artery Aneurysm: Surgery and GDC Embolization Group

OBJECTIVE: The authors present the difference of cognitive outcome of good recovery patients between direct surgery and Guglioma detachable coil(GDC) embolization group among anterior communicating artery aneurysm patients. METHODS: The clinical records of 21 patients who can be followed up and be answered questionnaires among good recovery patients fter ACoA(anterior communicating artery) aneurysm operation from 1990 to 1999 in our hospital were reviewed as surgery group. On the other hand, 20 good recovery patients after embolization of ACoA aneurysm in the other hospital from 1996 to 1999 are seleted as GDC embolization group. In the surgery group, the degree of brain swelling, the existence of rectus gyrus removal, existence of immediate post operative transient neurological deficit and the post operative brain CT findings are examined. In GDC embolization group, problem during embolization, existence of immediate post operative transient neurological deficit and the post operative brain CT findings are also investigated. After this investigation, patients and their family are questioned with Tidwell's cognitive outcome paper. The total records below 50 were considered as poor outcome. RESULTS: Ages, sex, Hunt and Hess grade, Fisher grade and size of aneurysm in two groups are similar conditions. The more patients get old, the cognitive outcome is worse in both group. In surgery group, those patients who have giant aneurysm, are removed rectus gyrus, are happened immediate post-operative transient neurological deficits and hypodense area in post operative brain CT are poor cognitive outcome. In the embolization group, Fisher grade III and post operative transient neurological deficit are happened, outcome was poor. In comparison with cognitive outcome between surgery and GDC embolization group, the embolization group has generally good result. CONCLUSION: The cognitive outcome is decided by age and the degree of brain injury according to aneurysmal rupture. Direct surgery method can make cognitive outcome poor due to perforator injury, brain retraction injury and removal of rectus gyrus during surgery, in the neuropsychological side and the GDC embolization is the better way than the direct surgery method.

The Quality of Life and Cognitive Deficits According to Treatment Modality of Anterior Communicating Artery Aneurysm: Surgery and GDC Embolization Group

OBJECTIVE: The authors present the difference of cognitive outcome of good recovery patients between direct surgery and Guglioma detachable coil(GDC) embolization group among anterior communicating artery aneurysm patients. METHODS: The clinical records of 21 patients who can be followed up and be answered questionnaires among good recovery patients fter ACoA(anterior communicating artery) aneurysm operation from 1990 to 1999 in our hospital were reviewed as surgery group. On the other hand, 20 good recovery patients after embolization of ACoA aneurysm in the other hospital from 1996 to 1999 are seleted as GDC embolization group. In the surgery group, the degree of brain swelling, the existence of rectus gyrus removal, existence of immediate post operative transient neurological deficit and the post operative brain CT findings are examined. In GDC embolization group, problem during embolization, existence of immediate post operative transient neurological deficit and the post operative brain CT findings are also investigated. After this investigation, patients and their family are questioned with Tidwell's cognitive outcome paper. The total records below 50 were considered as poor outcome. RESULTS: Ages, sex, Hunt and Hess grade, Fisher grade and size of aneurysm in two groups are similar conditions. The more patients get old, the cognitive outcome is worse in both group. In surgery group, those patients who have giant aneurysm, are removed rectus gyrus, are happened immediate post-operative transient neurological deficits and hypodense area in post operative brain CT are poor cognitive outcome. In the embolization group, Fisher grade III and post operative transient neurological deficit are happened, outcome was poor. In comparison with cognitive outcome between surgery and GDC embolization group, the embolization group has generally good result. CONCLUSION: The cognitive outcome is decided by age and the degree of brain injury according to aneurysmal rupture. Direct surgery method can make cognitive outcome poor due to perforator injury, brain retraction injury and removal of rectus gyrus during surgery, in the neuropsychological side and the GDC embolization is the better way than the direct surgery method.

Complications in Endovascular Surgery for Aneurysm / 대한뇌혈관학회지

The most important assets of a responsible and successful neuro-endovascular surgeon are knowledge of the possible technical difficulties, complications that may be encountered during the procedures. The intrinsic risks of complications involved with GDC embolization for cerebral aneurysms are multifactorial; the experience and skill of the physician, the different kind of devices used and geometry of aneurysm. Any complication can be totally unpredictable and even unknown for a time. Duration of the procedures another critical factor, so some of the complications (eg., vascular damage, thrombosis, intimal damage) is simply from the length of the procedure.