Efficacy of temozolomide treatment in patients with high-grade glioma.

BACKGROUND: Numerous studies have reported the clinical efficacy of temozolomide (TMZ) treatment for high-grade glioma, but information on Japanese populations has been limited. This study assessed the safety and early outcomes of TMZ treatment, with or without combination therapy. PATIENTS AND METHODS: The subjects comprised ten patients with high-grade glioma [glioblastoma multiforme (GBM), n=3, gliosarcoma (GS), n=1, anaplastic oligodendroglioma (AO), n=3, anaplastic mixed oligoastrocytoma (AOA), n=1, and anaplastic ependymoma (AE), n=2]. All the patients were initially treated with conventional radiotherapy following surgical resection with or without adjuvant chemotherapy. As second- or third-line chemotherapy, patients received TMZ for recurrence or tumor progression. As combination therapy, the local administration of tumor necrosis factor-alpha and the addition of carboplatin and etoposide were included for three patients during the course of oral TMZ treatment. RESULTS: Partial response (PR) to TMZ therapy was achieved by four out of the ten patients (objective response rate, 40%), while three patients displayed stable disease (SD) and three showed disease progression (PD). One of the patients receiving combination therapy has continued to show shrinkage of the relapsed tumor. Despite prior radio- and chemotherapy, most patients experienced only grade 1-2 hematotoxicity that was well-controlled by conservative therapy. CONCLUSION: TMZ chemotherapy is effective for the treatment of high-grade glioma in some patients without serious toxicity. Assessing the true efficacy of TMZ will require a larger study with comparison of long-term outcomes between other agents or combined therapeutic modalities.

Metastatic adenocarcinoma in the brain: magnetic resonance imaging with pathological correlations to mucin content.

BACKGROUND: Hypointense signal appearance of metastatic adenocarcinoma on T2-weighted imaging (T2-WI) has been infrequently documented. The purpose of this report was to evaluate the degree to which mucin content affects signal manifestations on conventional MR imaging. PATIENTS AND METHODS: This series of 24 cases with intracerebral metastatic adenocarcinoma was assessed retrospectively, focusing on the association between hypointense appearance on T2-WI and intratumoral mucin content. RESULTS: Among the 24 metastatic adenocarcinomas, intratumoral mucin was histopathologically confirmed in 8 lesions. Of these, 4 masses were demonstrated as hyperintense signal on T2-WI. The other 4 masses were depicted as isointensity. No cases were identified with hypointense signals in mucin-containing metastatic adenocarcinoma. Conversely, only 2 metastatic tumors originating from the stomach exhibited hypointense signal lesions on T2-WI. No histological or magnetic resonance imaging evidence of blood products or other forms of iron were identified as causes of the hypointense appearance on T2-WI. CONCLUSION: This hypointense signal may simply reflect the relatively shorter T2 relaxation time of the primary tissue from which metastases arose. Intratumoral mucin itself may be considered to demonstrate the masses as hyper- or isointense signals in the brain.

Quantitative assessment of gliomas by proton magnetic resonance spectroscopy.

BACKGROUND: Advanced magnetic resonance (MR) techniques provide physiological and metabolic information that complements the anatomical information available from conventional MR imaging. The purpose of this study was to evaluate the clinical usefulness of proton MR spectroscopy (1H-MRS) in preoperative quantitative assessment of intracranial gliomas. PATIENTS AND METHODS: Eight patients with histologically verified gliomas, comprising 2 cases with glioblastoma multiforme (GBM, grade 4), 5 cases with anaplastic oligodendroglioma (AO, grade 3; high-grade glioma), and 1 case with fibrillary astrocytoma (FA, grade 2; low-grade glioma) were evaluated using the 1H-MRS protocol following conventional MR imaging, diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI) preoperatively. RESULTS: High-grade gliomas tended to demonstrate signal hyperintensity by DWI and higher relative cerebral blood volume (rCBV) by PWI. Increased ratios of choline (Cho) to N-acetylaspartate (NAA) (Cho/NAA) and Cho to creatine (Cr) (Cho/Cr) correlated highly with tumor malignancy. The presence of lactate and lipid was predominately detected in patients with high-grade glioma. CONCLUSION: The combination of multiple MR parameters, based on DWI, PWI and 1H-MRS, appears valuable for preoperatively predicting the degree of malignancy in glioma.

[Ruptured aneurysm of distal posterior inferior cerebellar artery located at caudal loop].

We report an unusual case of subarachnoid hemorrhage (SAH) due to ruptured aneurysm originating at the caudal loop of posterior inferior cerebellar artery (PICA). The patient was a 77-year-old female presented with a sudden onset of headache and vomiting. Initial CT scan demonstrated a SAH with thick hematoma mainly in the cisterna magna. Vertebral angiogram revealed a saccular aneurysm arising from the tonsillomedullary segment of the left PICA, and communicating artery with supplying a territory of contralateral vermis as an anastmotic vessel. At surgery, no vessel branches were confirmed in the vicinity of the aneurysm, and this aneurysm was successfully clipped. In the fetus, numerous basilar and vertebral arteries are organized in plexiform formations around the brain stem. It has been suggested that the pathogenesis of such aneurysm or communicating artery could be related with a remnant of a primitive vertebrobasilar anastomosis. Based on these considerations, congenital vessel-wall weakness and hemodynamic stress associated with communicating artery may contribute to the development of distal PICA aneurysms.

[Unilateral sudden deafness as a primary symptom of brainstem and cerebellar infarction].

We report a case with a unilateral sudden sensorineural hearing loss caused by an infarction of brainstem and cerebellum. The patient was a 74-year-old male presented with a sudden onset of hearing loss and tinnitus in the right ear and dizziness. Steroid was administered on suspicion of idiopathic sudden deafness. However, the initial symptoms were deteriorated approximately 2 weeks later. He newly complained of the numbness of the right face and double vision, and he was transferred to our hospital for further evaluation. Neurological examination demonstrated horizontal nystagmus, diminution in the right facial sensation, right peripheral facial palsy, right hearing loss and cerebellar ataxia. Urgent MRI disclosed fresh infarctions of the right middle cerebellar peduncle and cerebellum localized in the territory of anterior inferior cerebellar artery. In general, idiopathic sudden deafness and Meniere's disease are frequent diagnosis in cases of sudden hearing loss with vertigo, but these symptoms may rarely be caused by cerebrovascular disorder. In patients with risk factors for arteriosclerosis, cerebrovascular disorder should be taken into consideration even if idiopathic sudden deafness may be suspected clinically. We emphasize the diagnostic importance of careful observation on neurological findings and early detection of radiological abnormalities on MRI.

Functional structure and antimicrobial activity of persulcatusin, an antimicrobial peptide from the hard tick Ixodes persulcatus.

BACKGROUND: Antimicrobial peptides (AMPs) are considered promising candidates for the development of novel anti-infective agents. In arthropods such as ticks, AMPs form the first line of defense against pathogens in the innate immune response. Persulcatusin (IP) was found in the Ixodes persulcatus midgut, and its amino acid sequence was reported. However, the complete structure of IP has not been identified. We evaluated the relation between structural features and antimicrobial activity of IP, and its potential as a new anti-methicillin-resistant Staphylococcus aureus (MRSA) agent. METHODS: The structure of IP was predicted using homology modeling and molecular dynamics. IP and other tick AMPs were synthesized using a solid-phase method and purified by high-performance liquid chromatography. Methicillin-susceptible S. aureus (MSSA) and MRSA were used for the minimum inhibitory concentration (MIC) test and short-time killing assay of IP and other tick peptides. The influence of IP on mammalian fibroblasts and colon epithelial cells and each cell DNA and its hemolytic activity towards human erythrocytes were also examined. RESULTS: In the predicted IP structure, the structure with an S-S bond was more stable than that without an S-S bond. The MIC after 24 h of incubation with IP was 0.156-1.25 µg/mL for MSSA and 0.625-2.5 µg/mL for MRSA. Compared with the mammalian antimicrobial peptide and other tick peptides, IP was highly effective against MRSA. Moreover, IP showed a dose-dependent bactericidal effect on both MSSA and MRSA after 1 h of incubation. IP had no observable effect on mammalian cell growth or morphology, on each cell DNA and on human erythrocytes. CONCLUSIONS: We predicted the three-dimensional structure of IP and found that the structural integrity was maintained by three S-S bonds, which were energetically important for the stability and for forming α helix and ß sheet. IP has cationic and amphipathic properties, which might be related to its antimicrobial activity. Furthermore, the antimicrobial activity of IP against MRSA was stronger than that of other antimicrobial peptides without apparent damage to mammalian and human cells, demonstrating its possible application as a new anti-MRSA medicine.

Fluctuations in free or substrate-complexed lysozyme and a mutant of it detected on x-ray crystallography and comparison with those detected on NMR.

A mutant lysozyme in which Arg14 and His15 were deleted together exhibited higher activity toward glycol chitin than the wild-type lysozyme. Moreover, the mutant lysozyme, which is less stable than the wild-type lysozyme by 7 degrees C, showed a shift of temperature dependence of activity to the low temperature side compared with the wild-type lysozyme [Protein Eng. 7, 743-748 (1994)]. In the free enzyme, the internal motion of the mutant lysozyme was similar to that of the wild-type. The internal motions of the wild-type and mutant lysozymes in the enzyme-substrate complex increased more than those in the free enzymes. Moreover, the increased internal motions of the substrate-complexed mutant lysozyme were greater than those of the substrate-complexed wild-type lysozyme in several residues [J. Mol. Biol. 286, 1547-1565 (1999)]. The structure of the mutant lysozyme was very similar to that of the wild-type lysozyme. Both structures were also alike in the complex of the trimer of N-acetyl-D-glucosamine. The mobility from B-factors agreed to some degree with that from order parameters in the regions showing great mobility of the protein, but this was not the case in the regions showing fast motion. However, we came to the same conclusion that the increased activity of the mutant lysozyme is due to the increase in the fluctuation of the lysozyme molecule. B-factor and order parameter do not always exhibit harmony because the time-scale of the analysis of mobility is different. However, they are not incompatible but complementary for detecting precise protein motions.

Sonodynamic therapy with 5-aminolevulinic acid and focused ultrasound for deep-seated intracranial glioma in rat.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) has already been applied clinically as a photosensitizer. In this study, sonodynamically induced selective antitumour effect of 5-ALA for deep-seated lesions was evaluated. MATERIALS AND METHODS: First, normal rat brains were sonicated via a transducer placed on the dural surface to confirm safe acoustic conditions for normal rat brains. One week after inoculation of brains with C6 rat glioma cells, brains with/without administration of 5-ALA (100 mg/kg body weight) were sonicated. RESULTS: Sonodynamic therapy (SDT) with 5-ALA and focused ultrasound (10 W/cm(2), 1.04 MHz, 5 min) achieved selective antitumour effect against deep-seated experimental glioma. Mean tumour sizes in the largest coronal section in sham-operated rats and rats receiving ultrasound with/without 5-ALA were 29.94±10.39, 18.32±5.69 and 30.81±9.65 mm(2), respectively. Tumour size was significantly smaller in the SDT group than in other groups (p<0.05). CONCLUSION: This experimental rat model showed that SDT appears to be useful in the treatment of deep-seated malignant glioma.

Subependymoma with prominent rosenthal fiber formation: case report.

A 62-year-old woman presented with a rare case of subependymoma associated with prominent Rosenthal fibers located in the left lateral ventricle manifesting as right hemiparesis and mild motor aphasia. The tumor was well demarcated and consisted of clusters of round nuclei embedded in an abundant gliofibrillary matrix with some microcysts and prominent Rosenthal fibers. Immunohistochemically, the tumor stained positively for glial fibrillary acidic protein and negatively for synaptophysin. This case of subependymoma containing Rosenthal fiber formation is very unusual.

Endoscopic management of a traumatic meningo-encephalocele through a planum sphenoidale defect: case report.

A 37-year-old man involved in a motor vehicle accident was admitted to our hospital with disturbed consciousness. Computed tomography (CT) showed an acute, right-sided epidural hematoma and pneumocephalus. Emergency evacuation of the acute epidural hematoma was carried out, and his condition gradually recovered. However, cerebrospinal fluid (CSF) rhinorrhea continued despite conservative treatment. Three-dimensional reconstructed CT revealed a bone defect, which was approximately 20 mm in size, in the planum sphenoidale and tuberculum sellae, and magnetic resonance imaging demonstrated a traumatic meningo-encephalocele through the defect, with CSF collection in the sphenoid sinus. Endoscopic endonasal transsphenoidal surgery was performed. The 9-mm diameter dural defect was clearly visualized in the sphenoid sinus and was reconstructed with a combination of suturing and overlay with abdominal fascia, and absorbable polyglycolic acid felt. The CSF leakage from a traumatic meningo-encephalocele through the planum sphenoidale was successfully repaired by endoscopic endonasal surgery. Thorough preoperative evaluation of the feasibilities of the endoscopic and transcranial approaches should be based on the preoperative identification of the fistula, the bone defect, and vital structures.

Cavernous malformation of the ventral midbrain successfully removed via a transsylvian-transpeduncular approach: case report.

A 37-year-old woman presented with a rare cavernous malformation of the ventral midbrain with brainstem hemorrhage manifesting as sudden onset of headache and vomiting. The lesion was removed successfully through a transsylvian approach and a medial peduncular route. Postoperatively, her oculomotor nerve paresis worsened temporarily, but diplopia disappeared 2 months after surgery. We recommend the transsylvian-transpeduncular approach if the lesion is located in the ventral midbrain and faces the ventral surface of the brainstem, because of the effective access with minimal neurological deficits.

[Ruptured aneurysm of distal posterior inferior cerebellar artery located at caudal loop].

We report an unusual case of subarachnoid hemorrhage (SAH) due to ruptured aneurysm originating at the caudal loop of posterior inferior cerebellar artery (PICA). The patient was a 77-year-old female presented with a sudden onset of headache and vomiting. Initial CT scan demonstrated a SAH with thick hematoma mainly in the cisterna magna. Vertebral angiogram revealed a saccular aneurysm arising from the tonsillomedullary segment of the left PICA, and communicating artery with supplying a territory of contralateral vermis as an anastmotic vessel. At surgery, no vessel branches were confirmed in the vicinity of the aneurysm, and this aneurysm was successfully clipped. In the fetus, numerous basilar and vertebral arteries are organized in plexiform formations around the brain stem. It has been suggested that the pathogenesis of such aneurysm or communicating artery could be related with a remnant of a primitive vertebrobasilar anastomosis. Based on these considerations, congenital vessel-wall weakness and hemodynamic stress associated with communicating artery may contribute to the development of distal PICA aneurysms.

Decreased phenobarbital absorption with charcoal administration for chronic renal failure.

OBJECTIVE: To report a case of impaired absorption of orally administered phenobarbital associated with the concomitant administration of activated charcoal, and recovery of the absorption after administration of the 2 drugs was separated by a 1.5-hour interval. CASE SUMMARY: A 78-year-old woman, weighing 50 kg, who had undergone brain surgery was prescribed phenobarbital 120 mg/day for postoperative convulsions. Her serum phenobarbital concentration reached 24.8 microg/mL (therapeutically effective level 10-30). Thereafter, her renal function worsened, and activated charcoal 6 g/day was started. Four months after the start of activated charcoal, blood analysis revealed that the serum phenobarbital concentration was as low as 4.3 microg/mL. The phenobarbital dose was increased to 150 mg/day. Further evaluation revealed that activated charcoal and phenobarbital had been administered concomitantly. The dosage regimen was altered to separate the administration of the agents by at least 1.5 hours. Subsequently, the patient's serum phenobarbital concentration increased to 11.9 microg/mL within 3 weeks. Her serum phenobarbital concentration was measured monthly thereafter and remained stable in the range of 14.8-18.6 microg/mL. DISCUSSION: Our patient's low serum phenobarbital concentration was considered likely to have been due to impaired gastrointestinal absorption of phenobarbital as a result of adsorption of phenobarbital on the activated charcoal. An objective causality assessment showed that the interaction was probable. CONCLUSIONS: Administration of activated charcoal and phenobarbital should be separated by an interval of at least 1.5 hours.

A nucleotide switch in the Escherichia coli DnaA protein initiates chromosomal replication: evidnece from a mutant DnaA protein defective in regulatory ATP hydrolysis in vitro and in vivo.

The ATP-bound DnaA protein opens duplex DNA at the Escherichia coli origin of replication, leading to a series of initiation reactions in vitro. When loaded on DNA, the DNA polymerase III sliding clamp stimulates hydrolysis of DnaA-bound ATP in the presence of the IdaB/Hda protein, thereby yielding ADP-DnaA, which is inactive for initiation in vitro. This negative feedback regulation of DnaA activity is proposed to play a crucial role in the replication cycle. We here report that the mutant protein DnaA R334A is inert to hydrolysis of bound ATP, although its affinities for ATP and ADP remain unaffected. The ATP-bound DnaA R334A protein, but not the ADP form, initiates minichromosomal replication in vitro at a level similar to that seen for wild-type DnaA. When expressed at moderate levels in vivo, DnaA R334A is predominantly in the ATP-bound form, unlike the wild-type and DnaA E204Q proteins, which in vitro hydrolyze ATP in a sliding clamp- and IdaB/Hda-dependent manner. Furthermore, DnaA R334A, but not the wild-type or the DnaA E204Q proteins, promotes overinitiation of chromosomal replication. These in vivo data support a crucial role for bound nucleotides in regulating the activity of DnaA during replication. Based on a homology modeling analysis, we suggest that the Arg-334 residue closely interacts with bound nucleotides.