Emerging Surgical Strategies of Intractable Frontal Lobe Epilepsy with Cortical Dysplasia in Terms of Extent of Resection

OBJECTIVE: Cortical dysplasia (CD) is one of the common causes of epilepsy surgery. However, surgical outcome still remains poor, especially with frontal lobe epilepsy (FLE), despite the advancement of neuroimaging techniques and expansion of surgical indications. The aim of this study was to focus on surgical strategies in terms of extent of resection to improve surgical outcome in the cases of FLE with CD. METHODS: A total of 11 patients of FLE were selected among 67 patients who were proven pathologically as CD, out of a total of 726 epilepsy surgery series since 1992. This study categorized surgical groups into three according to the extent of resection : 1) focal corticectomy, 2) regional corticectomy, and 3) partial functional lobectomy, based on the preoperative evaluation, in particular, ictal scalp EEG onset and/or intracranial recordings, and the lesions in high-resolution MRI. Surgical outcome was assessed following Engel's classification system. RESULTS: Focal corticectomy was performed in 5 patients and regional corticectomy in another set of 5 patients. Only 1 patient underwent partial functional lobectomy. Types I and II CD were detected with the same frequency (45.45% each) and postoperative outcome was fully satisfactory (91%). CONCLUSION: The strategy of epilepsy surgery is to focus on the different characteristics of each individual, considering the extent of real resection, which is based on the focal ictal onset consistent with neuroimaging, especially in the practical point of view of neurosurgery.

Aberrant CpG Islands Hypermethylation Profiles in Malignant Gliomas

BACKGROUND: The authors analyzed whether the promoter hypermethylation of cancer-related genes was involved in the tumorigenesis of malignant gliomas. METHODS: A total of 29 patients received surgery and histologically confirmed to have malignant gliomas from January 2000 to December 2006. The promoter methylation status of several genes, which were reported to be frequently methylated in malignant gliomas, was investigated using methylation-specific polymerase chain reaction. RESULTS: All cases of malignant gliomas represented the promoter hypermethylation in at least 2 or more genes tested. Of 29 tumors, 28 (96.55%) showed concurrent hypermethylation of 3 or more genes. Ras association domain family member 1, epithelial cadherin, O-6 methyl guanine DNA methyltransferase, thrombospondin 1, p14 and adenomatous polyposis coli were frequently methylated in high grade gliomas including glioblastomas, anaplastic astrocytomas, and anaplastic oligodendrogliomas. CONCLUSION: Aberrant hypermethylation profile was closely related with malignant gliomas suggesting that epigenetic change may play a role in the development of malignant gliomas. Two or three target genes may provide useful clues to the development of the useful prognostic as well as diagnostic assays for malignant gliomas.

Comparison between Initial and Recent Surgical Outcome of 15-Year Series of Surgically Remediable Epilepsy

OBJECTIVE: The aim of this study is to compare the surgical outcome of the initial and recent surgical cases, during our 15-years experience, in terms of the surgical strategies and the prognostic factors for surgically remediable epilepsy. METHODS: We retrospectively reviewed and compared the surgical outcomes between the initial 256 (Group I) and recent 139 (Group II) patients according to the time period of operation for a total of 518 consecutive epilepsy surgeries at our institution since 1992. The patients of the middle intermediate period, which were subjected to changed surgical strategies, were excluded. RESULTS: The surgical outcome data from the initial and recent groups showed a much improved outcome for patients who underwent temporal lobe epilepsy (TLE) surgery over time. The number of patients with a good outcome (Engel class I-II) was much increased from 87.7% (178 TLE cases of Group I) to 94.8% (79 TLE cases of Group II) and this was statistically significant (p = 0.0324) on univariate analysis. Other remarkable changes were the decreased performance of intracranial invasive studies from 43.5% in Group I to 30.9% in Group II due to the advanced neuroimaging tools. The strip/grid ratio was reduced from 131/32 in Group I to 17/25 in Group II, because of a markedly reduced mesial TLE surgery and an increased extratemporal epilepsy surgery. CONCLUSION: Our results show that surgical outcome of epilepsy surgery has improved over time and it has shown to be efficient to control medically intractable epilepsy. Appropriate patient selection, comprehensive preoperative assessments and more extensive resection are associated with good postoperative outcomes.

Intracranial Fusiform Aneurysms: It's Pathogenesis, Clinical Characteristics and Managements

OBJECTIVE: The objective of this study is to investigate clinical characteristics, management methods and possible causes of intracranial fusiform aneurysm. METHODS: Out of a series of 2,458 intracranial aneurysms treated surgically or endovascularly, 22 patients were identified who had discrete fusiform aneurysms. Clinical presentations, locations, treatment methods and possible causes of these aneurysms were analyzed. RESULTS: Ten patients of fusiform aneurysm were presented with hemorrhage, 5 patients with dizziness with/without headache, 4 with ischemic neurologic deficit, and 1 with 6th nerve palsy from mass effect of aneurysm. Two aneurysms were discovered incidentally. Seventeen aneurysms were located in the anterior circulation, other five in the posterior circulation. The most frequent site of fusiform aneurysm was a middle cerebral artery. The aneurysms were treated with clip, and/or wrapping in 7, resection with/without extracranial-intracranial (EC-IC) bypass in 6, proximal occlusion with coils with/without EC-IC bypass in 5, EC-IC bypass only in 1 and conservative treatment in 3 patient. We obtained good outcome in 20 out of 22 patients. The possible causes of fusiform aneurysms were regard as dissection in 16, atherosclerosis in 4 and collagen disease or uncertain in 2 cases. CONCLUSION: There is a subset of cerebral aneurysms with discrete fusiform morphology. Although the dissection or injury of internal elastic lamina of the cerebral vessel is proposed as the underlying cause for most of fusiform aneurysm, more study about pathogenesis of these lesions is required.

Cerebellar Ganglioglioma

The location of ganglioglioma (GG) within the infratentorial compartment is unusual. The authors report a rare case of GG in the cerebellar hemisphere. A 12-year-old boy suffered from headache and gait disturbance. Neuroimaging studies demonstrated a large enhancing cerebellar mass with cystic components compressing the forth ventricle. After complete resection of the tumor, the patient became symptom free. Histological examination on the tumor disclosed glial cells and dysplastic ganglion cells. Although it is a rare tumor, in the appropriate clinical setting, a GG should be considered in the presence of a cerebellar mass with both solid and cystic components on magnetic resonance images in children.

Expression of Cancer-Testis Genes in Brain Tumors

OBJECTIVE: Cancer-testis (CT) genes are considered promising candidates for immunotherapeutic approaches. The aim of this study was to investigate which CT genes should be targeted in immunotherapy for brain tumors. METHODS: We investigated the expression of 6 CT genes (MAGE-E1, SOX-6, SCP-1, SSX-2, SSX-4, and HOMTES-85) using reverse-transcription polymerase chain reaction in 26 meningiomas and 32 other various brain tumor specimens, obtained from the patients during tumor surgery from 2000 to 2005. RESULTS: The most frequently expressed CT genes of meningiomas were MAGE-E1, which were found in 22/26 (85%) meningioma samples, followed by SOX-6 (9/26 or 35%). Glioblastomas were most frequently expressed SOX-6 (6/7 or 86%), MAGE-E1 (5/7 or 71%), followed by SSX-2 (2/7 or 29%) and SCP-1 (1/7 or 14%). However, 4 astrocytomas, 3 anaplastic astrocytomas, and 3 oligodendroglial tumors only expressed MAGE-E1 and SOX-6. Schwannomas also expressed SOX-6 (5/6 or 83%), MAGE-E1 (4/6 or 67%), and SCP-1 (2/6 or 33%). CONCLUSION: The data presented here suggest that MAGE-E1 and SOX-6 genes are expressed in a high percentage of human central nervous system tumors, which implies the CT genes could be the potential targets of immunotherapy for human central nervous system tumors.

Development of Korean Model for Independent Organ Procurement Organization / 대한이식학회지

PURPOSE: The aims of this project were to increase organ donation by developing potential brain dead donor actively and to provide basic data to settle up independent Organ Procurement Organization (OPO) in Korea. METHODS: Hospital based Organ Procurement Organization (HOPO) of Keimyung university worked as a regional OPO and all the reported potential brain dead patient were treated by OPO team during May through October, 2007. Every reported and confirmed brain dead patient was evaluated for their eligibility of organ donation and these organs were allocated by Korean Network for Organ Sharing (KONOS). In order to increase the development of organ donation, campaign was done for public and medical personnels. To estimate the capacity of brain death donor pool, medical records of the dead patients with brain injury were evaluated. Accommodations and educations to the care-giver to the potential donor, neurosurgeon, neurologist and emergency department physicians were also done. For standardization of potential donor care, frame a clinical pathway of the care of the potential donor from the data of computerized records. The cash flow of whole process from developing potential donor to final procurement of organs were calculated to provide minimum expenses for operating Independent OPO in our environment. RESULTS: Total 33 solid organs were procured from 11 brain dead donor during the experimental period. Twelve more organs were possible to donate but not procured because there were no matched recipient at that time. The reported number of potential donor was increased 2.5 times, compare to the same period of previous year (19 from 5 hospital in 2006 but 47 from 14 collaborating hospitals in 2007). Among 47 notified potential donor, only 11 were succeeded to procure. The reasons of failure for procurement in 36 patients were no familial consent in 12, poor patient condition to donate in 9, not in brain death criteria in 15. These results mean that we have at least 21 more potential donors if we can get familial consent and use marginal donor, and early notification. Mean medical expenses were 3 million won for individual expense beside insurance coverage and 5 million won for management expense of donor care from the detection to organ procurement. CONCLUSION: Our results showed the number of the potential donor and actual organ donation can be increased by continued active relationship with regional hospital and adequate care of the donor. The big gap between the profit from our donor care and calculated donor management expenses of IOPO can be progressively covered by increasing number of brain dead donor, increasing procurement rate and increasing organ fee paid by recipient. But for a certain periods, financial support is necessary to settle up IOPO. Our result can be used as a basic data for management plan of IOPO in the future.

Clinical Features and Surgical Treatment of Bacterial Brain Abscess

OBJECTIVES: This study was performed to review the clinical characteristics and operative results of brain abscess in order to define the therapeutic strategy for this disease. METHODS: We reviewed the medical records and radiology images of brain abscess patients treated in our hospital during the last 16 years. A total of 35 cases included 23 males and 12 females, with the mean age of 48 years old. We excluded cases of postoperative, post traumatic, and fungal abscess. All patient underwent at least one surgical treatment such as stereotactic aspiration or craniotomy with excision. RESULTS: Twenty seven (77.1%) patients presented with symptoms of increased intracranial pressure. The frontal lobe was the most common anatomical place, and streptococcal species were the most frequently encountered pathogens. The chronic pulmonary diseases and chronic otitis media are common underlying condition. Eighteen patients underwent stereotactic aspiration and 17 patients had excision of their abscess as an initial treatment. Seven patients had a repeated surgery, 6 of them had been treated with aspiration initially. At discharge, 60.0% patients showed a favorable outcome. CONCLUSION: The stereotactic drainage would be more suitable for the brain abscess located in deep and eloquent area. A large, solitary, and well-encapsulated lesion of superficial location could be best treated with complete excision, and this procedure was more definite because it is associated with less repeated surgery and showed more favorable outcome compared to aspiration surgery.

Microbleeds in Patients with Primary Intracerebral Hemorrhages

OBJECTIVE: We investigate risk factors of cerebral microbleeds(MBs) and their relation to concomitant magnetic resonance (MR) findings in intracerebral hemorrhages(ICHs) patients. METHODS: We studied 100 consecutive patients with primary ICH over a 1-year period. These patients underwent brain MR images using 3.0-T scanners within the first week of the hemorrhage. MBs and old hematomas were located and counted by using T2*-weighted gradient-echo MR imaging. We also counted lacunes and graded white matter and periventricular hyperintensity on T1- and T2-weighted spin-echo sequences. The association between MBs and vascular risk factors and MR abnormalities were analyzed. RESULTS: MBs were seen in 77 of ICH patients, and their number ranged from 1 to 65 lesions (mean 11, median 6). The locations of MBs were subcortex-cortex (40.6%), basal ganglia (26.7%), thalamus (14.1%), brain stem (12.5%), and cerebellum (9.1%). Analysis of clinical data revealed that age, hypertension, history of stroke, and duration of hypertension were frequently associated with MBs. The incidence of lacunes, old hematomas, and advanced leukoaraiosis was significantly higher in the MBs group, compared with the patients without MBs. CONCLUSION: MBs are frequently observed in ICH patients with advancing age, chronic hypertension, and previous hemorrhagic stroke, and are also closely related with morphological signs of occlusive type microangiopathy, such as lacunar infarct and severe leukoaraiosis.

Effects of Anterior Temporal Lobectomy for Mesial Temporal Lobe Epilepsy on Intellectual and Memory Functions: 1-Year Follow-up

BACKGROUND: The aim of this study was to identify factors predicting intellectual and memory changes following anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (TLE). METHODS: The sample consisted of 31 patients who underwent ATL for treatment of medically intractable TLE. All patients were administered intellectual and memory tests preoperatively and postoperatively. RESULTS: All statistically significant intellectual and memory changes at 1-year follow-up were in the direction of improvement. Left vs. right ATL had significantly differential effects on verbal intelligence and verbal memory, reflecting greater decline (or less improvement) following a left ATL. A later onset age of seizures, an older age at surgery, and a higher presurgical cognitive performance predicted a greater cognitive decline following an ATL. CONCLUSIONS: At 1-year after ATL, most cognitive functions showed either no significant changes or significant changes in a favorable direction. Decreased verbal functions following a left ATL was the area of greatest potential neuropsychological morbidity associated with ATL. Greater cognitive decline following ATL was predicted by later onset age of recurrent seizures, older age at time of surgery, and higher presurgical cognitive performance.

Treatment of Supratentorial Primitive Neuroectodermal Tumors (PNETs) in Children

OBJECTIVE: Strategies for managing supratentorial primitive neuroectodermal tumors(PNETs) in children include surgical resection, craniospinal irradiation and chemotherapy. This study is performed in order to compare the efficacy of various methods of treatment and to describe its optimal management. METHODS: We have reviewed all medical records and pathology slides of six children(four males and two females) with supratentorial PNET from November, 1987 to May, 2003. The extent of resection was confirmed by computed tomography and magnetic resonance studies. RESULTS: The patients were aged 1 to 13 years and treated postoperatively with/without adjuvant therapy. Tumor location included was four cortical, one gangliobasal, and one pineal region. The presenting symptoms and signs consisted of increased intracranial pressure and focal neurological deficits such as seizure and hemiparesis. The treatment consisted of surgical resection alone in one patient, postoperative radiotherapy in one patient, postoperative chemotherapy in one, and postoperative radiotherapy with chemotherapy in three. Five patients lived more than 12 months after diagnosis and one patient among them has been living more than 5 years after diagnosis. CONCLUSION: We can improve the survival and prognosis of supratentorial PNET patients by radical gross total resection of tumor followed by craniospinal irradiation and aggressive chemotherapy. First of all, gross total resection of tumor is the most important among many factors.

Treatment of Scalp Arteriovenous Malformation

OBJECTIVE: The object of this study is to present the treatment experience of the 6cases of scalp arteriovenous malformations(AVMs) focus on treatment strategy. METHODS: Six patients with scalp AVM were treated during past 12years. We analysis the clinical characteristics of the lesions, treatment methods and management outcomes. RESULTS: The lesions were located on temporal in 2 patients, parietal in 2 patients, frontal and occipital area in each one. Four of six patients had a trauma history on scalp. The presenting symptoms were progressive enlarged pulsating mass with or without bruit. Four of the six lesions had the large fistula in the lesion. Two patients were treated with surgical resection alone, three patients with proximal feeding artery balloon(s) occlusion followed by surgical resection, and one patient with coil embolization through trans-venous route alone. We obtained good results in all patients. CONCLUSION: Most of scalp AVM can be completely cured by judicious selection and a combination of treatment modalities, i.e., surgery only, or embolization only, or embolization plus surgical therapy. Although embolization became a primary therapy for this sort of scalp AVM recently, the selection of treatment modality should be chose based on the size, angioarchitecture, and clinical presentations of the lesion.

Analysis of Corticospinal Tract Injury by Using the Diffusion Tensor Imaging of 3.0 T Magnetic Resonance in Patients with Hypertensive Intracerebral Hemorrhage

OBJECTIVE: The purpose of this study is to identify correlations between diffusion tensor imaging(DTI) and motor improvement by quantifying and visualizing the corticospinal tract on DTI to predict motor impairment in patients with hypertensive intracerebral hemorrhage(ICH). METHODS: Fifteen normal subjects and 7 patients with hypertensive ICH were examined and the latter were treated surgically. DTI was performed with a 3.0 T MRI. The region of interest(ROI) from the posterior limbs of both internal capsules was measured on a fractional anisotropy(FA) map, and the ratios of ROIs were calculated. Tractography, 3-dimensional DTI was then constructed. Motor impairment was assessed on admission and 2weeks after stroke by the Motricity Index(MI). The FA ratio, tractography and score on MI were analyzed for correlations. RESULTS: The FA ratio from the initial DTI did not show a linear correlation with motor impairment. However, after 2weeks, patients with high FA ratios showed high degrees of motor recovery, regardless of the initial severity, and patients with low FA ratios showed low recovery rates. Otherwise, a relationship between the amount of hematoma and the degree of motor recovery could not be determined. On tractography, injury of the corticospinal tract could be visualized and estimated 3-dimensionally. CONCLUSION: FA ratio analysis and tractography constructed from DTI may be useful in understanding corticospinal tract injury and in predicting the recovery from motor impairment in patients.

Ictal SPECT-guided Epilepsy Surgery in a Patient with Forme Fruste Tuberous Sclerosis

Tuberous sclerosis is an autosomal dominant disease characterised by hamartomas (tubers) in many organ systems and the four major intracranial manifestations including cortical tubers, white matter abnormalities, subependymal nodules and subependymal giant cell astrocytoma. But there is immense variability in the clinical presentation of tuberous sclerosis and many incomplete forms (formes frustes) exist. Almost all patients with tuberous sclerosis have seizures and mental retardation. The authors experienced a 7-year-old boy with medically intractable epilepsy without any skin lesion or mental retardation. In terms of surgical standpoint for determination of extent of resection, corticectomy on the overriding cortex of right premotor and lesionectomy of periventricular calcified lesion were performed according to ictal single photon emission computed tomography(SPECT), which showed hyperperfusion in the subcortical and calcified area. Histopathologic findings showed a few cytologically abnormal neurons with extensive gliosis, containing many Rosenthal fibers, reactive astrocytes and dense calcification, composing of abundant calcospherites which suggested forme fruste tuberous sclerosis. During the follow-up period of eighteen months, seizure was free after surgery.

Calcified Chronic Subdural Hematoma Associated with Intracerebral Hematoma

Calcified chronic subdural hematoma is relatively common, however, its rupture into the subcortical white matter is very rare. A 37-year-old patient with a large, calcified, chronic subdural hematoma which ruptured intracerebrally forming a frontal lobe hemorrhage is reported. Craniotomy for removal of the hematoma and calcification achieved marked reduction in seizure frequency.

Treatment for Recurrent Cerebral Aneurysm

OBJECTIVE: The aim of this study is to make a management strategy for the patients with recurrent cerebral aneurysm after surgery. METHODS: Over a 19-year period, 1, 546 patients were treated for a ruptured intracranial aneurysm surgically. Twenty-six of these patients(1.7%) were subsequently treated for regrowing aneurysm(8) or de novo aneurysm formation(26). Among them, twenty-three individuals who presented with recurrent subarachnoid hemorrhage underwent conventional angiography to detect the aneurysm recurrence. Three-dimensional computed tomographic angiography was performed in the remaining three patients who complained chronic headache. The mean age at the first surgery was 48.6 years. An interval ranging from 1 to 192 months(mean, 76.1 months) since the original treatment. RESULTS: Total 34 recurrent aneurysms in 26 patients were treated by microsurgical clipping(29 cases), wrapping(1 case), and endovascular coiling(4 cases) as a second procedure. A satisfactory outcomes were achieved in twenty-one patients(80.8%) during a mean 69.5 months follow-up period. The most common site of the recurrence was the internal carotid-posterior communicating artery. Patients with de novo aneurysms are frequently hypertensive(61.1%) and younger in age(55.6%). CONCLUSION: The treatment of recurrent cerebral aneurysm could be performed effectively using direct operations and/or endovascular procedures.

Enhanced Focus in Hypertensive Intracerebral Hematoma on CT Scan and Hematoma Enlargement / 대한뇌혈관외과학회지

OBJECTIVE: Although most of hypertensive intracerebral hematoma (HICH) are static after ictus, a minority of them can enlarge in the acute phase after onset. This study performs to find the predicting factors and signs of hematoma enlargement in patients with HICH. METHODS: Among 140 cases of HICH treated during 1.5 years, the authors selected 107 cases who underwent contrast enhanced and nonenhanced initial CT scanning within 12 hours after symptom onset and a follow-up CT scan in order to investigate the enlargement of hematoma. Those cases were divided into two groups:hematoma enlargement (group I) and non-enlargement group (group II). The comparison of predicting factors (bleeding tendency, abnormal liver function and blood pressure) and signs (enhanced focus in hematoma on CT) of hematoma enlargement between group I and II was performed. RESULTS: There were 8 cases in group I and 99 cases in group II. The incidence of an enhanced focus in hematoma on CT scan was higher in group I than group II (87.5% vs. 9.1%, p<0.05). The systolic blood pressure (BP) at 6 hours after symptom onset and at the time of the first CT scan was higher in group I than group II (172.5 vs. 152.0 mm Hg, and 182.5 vs. 158.6 mm Hg, respectively, p<0.05). There was no difference in the incidence of bleeding tendency and abnormal liver function between group I and II. CONCLUSION: Contrast enhanced brain CT scan to detect the enhanced focus in the hematoma is one of useful methods to predict the early enlargement of hematoma in patients with HICH. The continuance of a high BP in spite of medication of antihypertensive drugs during the acute period after the onset of symptoms is another predictive sign of hematoma enlargement in patients with HICH.

Transnasal Repair of Traumatic Cerebrospinal Fluid Rhinorrhea

OBJECTIVE: This study is aimed to evaluate the efficacy of transnasal repair of cerebrospinal fluid(CSF) rhinorrhea. METHODS: Thirteen patients with traumatic noniatrogenic CSF fistulas were included in the retrospective analysis. High-resolution thin-section computed tomographic cisternography was helpful in localization of the CSF leakage site. The most frequent leakage site was the sphenoid sinus. The transnasal approach(TNA), comprised of endonasal endoscopic surgery(EES) or transseptosphenoidal surgery(TSS), was mainly used for smaller fistulas. Total or selected ethmoidectomy depended on the localization of the leakage. Wide sphenoidotomy enabled detection and repair of CSF leaks from the sphenoid cavity. Three patients also underwent transcranial approach(TCA) because of the large or multi-fragmented bony defect and the need for further exposure for repair. Five patients developed ascending meningitis in the preoperative period with antibiotic prophylaxis. RESULTS: Twenty-five leaks were initially repaired using one of three techniques:EES alone in eight patients, EES plus TCA in three, and TSS alone in two. Ten patients who solely underwent the TNA did not experience the complications of the traditional TCA. One recurrent sphenoid fistula was successfully treated by TSS. After a follow-up from 12 to 88 months(mean 32.7), the overall success rate for 25 CSF fistulas was 100%. CONCLUSION: The transnasal repair is a safe, successful, and alternative approach for the surgical repair of traumatic CSF rhinorrhea, and also could be combined to TCA.

Rebleeding of Cerebral Aneurysm during Three-Dimensional Computerized Tomographic Angiography

The authors report a 59-year-old woman who presented with diffuse subarachnoid hemorrhage and focal intracerebral hemorrhage in the right frontotemporal region with intraventricular hemorrhage after the right middle cerebral artery bifurcation aneurysmal rupture. The aneurysm was rebled during the 3-dimensional computerized tomographic angiography, which was performed 3 hours after initial attack. Although the aneurysm was successfully clipped, the patient died on the second hospital day. We discuss the risk factor of rebleeding of ruptured cerebral aneurysm and whether 3-dimensional computerized tomography angiography is a really safe method of detection of cerebral aneurysm in terms of rebleeding.

Alterations of 9p21-22 Region Encoding Genes in Primary Glioblastomas

BACKGROUND: Glioblastomas are one of the most common and aggressive malignant glial tumors occuring in the central nervous system. This study analyzed the status of p15INK4b, p14ARF, p16INK4a, MTAP, IFNA, and IFNB genes in 36 primary glioblastomas to investigate whether the inactivation of these genes participate in primary glioblastoma tumorigenesis. METHODS: We used polymerase chain reaction, polymerase chain reaction/single strand conformational polymorphism (PCR/SSCP) analysis, and methylation-specific PCR. RESULTS: Homozygous deletions at the p16INK4a gene were detected in 11 cases (30.5%) of 36 primary glioblastomas, and the promoter hypermethylation was found in 3 cases (8.3%) of 36 primary glioblastomas. In mutational analysis for the p16INK4a gene by PCR/SSCP, there was no abnormal mobility-shifted band in 36 cases of primary glioblastomas. The overall frequency of p16INK4a alterations including homozygous deletion and promoter hypermethylation in 36 primary glioblastomas was 38.8% (14 of 36). Deletions of p15INK4b were noted in 4 cases (11.1%), whereas deletions of the p14ARF and MTAP genes were detected in 1 case of 36 cases of primary glioblastomas. But deletions of the INFA and B genes were not found. CONCLUSIONS: These results suggest that alterations of the p16INK4a gene can be important mechanisms of the tumorigenesis of primary glioblastomas, and the p16INK4a gene is inactivated by mechanisms including homozygous deletion and promoter hypermethylation.