Yeon-Lim Suh

Prognostic significance of c-Met expression in glioblastomas

The authors investigated whether expression of c‐Met protein in glioblastomas is associated with overall survival and biologic features representing tumor invasiveness in patients with glioblastomas.

Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral Neuropathy with Hearing Loss and Optic Neuropathy (CMTX5)

We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.

Cerebral perfusion changes in mesial temporal lobe epilepsy: SPM analysis of ictal and interictal SPECT

We examined cerebral perfusion changes in mesial temporal lobe epilepsy (mTLE) by the statistical parametric mapping of brain single photon emission computed tomography (SPECT) images of 38 mTLE patients and 19 normal controls. Ictal and interictal SPECTs were compared with control SPECTs by independent t test, and ictal and interictal SPECTs by paired t test. We evaluated the number of heterotopic neurons in temporal lobe white matter, white matter changes of the anterior temporal lobe (WCAT) and ictal hyperperfusion of the temporal stem (IHTS). Left mTLE showed interictal hypoperfusion in the ipsilateral hippocampus, bilateral thalami, and paracentral lobules. Right mTLE showed hypoperfusion in bilateral hippocampi, contralateral insula, bilateral thalami, and paracentral lobules. Both mTLEs showed ictal hyperperfusion in bilateral temporal lobes with ipsilateral predominance, and in the anterior frontal white matter bilaterally. By paired t test, ictal hyperperfusion was found in the ipsilateral temporal lobe, temporal stem, hippocampus, thalamus, putamen, insula, and bilateral precentral gyri, whereas ictal hypoperfusion was found in bilateral frontal poles and middle frontal gyri. Fifteen patients showed WCAT and 19 showed IHTS, a weak correlation was observed between WCAT and IHTS (r = 0.377, P = 0.02). WCAT was found to correlate with an early seizure onset age. In 35 patients, heterotopic neurons were found in the white matter of the resected temporal lobe, but the number of heterotopic neurons did not correlate with WCAT or IHTS. In summary, the cerebral perfusion patterns of mTLE suggest interictal hypofunction and ictal activation of the cortico-thalamo-hippocampal-insular network and ictal hypoperfusion of the anterior frontal cortex.

Effect of muscle activity and botulinum toxin dilution volume on muscle paralysis

The purpose of this study was to evaluate the effects of botulinum toxin A (BTX-A, Botox) dilution volume and post-injection exercise with electrical stimulation on muscle paralysis. We injected 10 units of BTX-A diluted with 0.1 ml (B1, n=8) or 0.5 ml (B5, n=8) normal saline into both gastrocnemius muscles of 16 New Zealand white rabbits; two controls received no BTX-A. After BTX-A injection, all rabbits received calf muscle stretching exercise and electrical stimulation for 2 hours on the left leg. The compound muscle action potential (CMAP) decrease was most pronounced at 1 week and progressive recovery was observed (i.e. recovery from paralysis, increase of CMAP). There was a significant decrease of CMAP amplitudes in the B5 group compared with the B1 group at week 1 and week 4 (p<0.001). Left limbs with stretching exercise and electrical stimulation showed lower CMAP amplitudes compared with control right limbs of all rabbits. To maximize the muscle paralysis effect of BTX-A, increasing dilution volume and performing post-injection stretching exercise with electrical stimulation may be a promising strategy for increasing the beneficial effect of BTX-A treatment. Future studies are needed to investigate the clinical application of this finding.The purpose of this study was to evaluate the effects of botulinum toxin A (BTX‐A, Botox) dilution volume and post‐injection exercise with electrical stimulation on muscle paralysis. We injected 10 units of BTX‐A diluted with 0.1 ml (B1, n=8) or 0.5 ml (B5, n=8) normal saline into both gastrocnemius muscles of 16 New Zealand white rabbits; two controls received no BTX‐A. After BTX‐A injection, all rabbits received calf muscle stretching exercise and electrical stimulation for 2 hours on the left leg. The compound muscle action potential (CMAP) decrease was most pronounced at 1 week and progressive recovery was observed (i.e. recovery from paralysis, increase of CMAP). There was a significant decrease of CMAP amplitudes in the B5 group compared with the B1 group at week 1 and week 4 (p<0.001). Left limbs with stretching exercise and electrical stimulation showed lower CMAP amplitudes compared with control right limbs of all rabbits. To maximize the muscle paralysis effect of BTX‐A, increasing dilution volume and performing post‐injection stretching exercise with electrical stimulation may be a promising strategy for increasing the beneficial effect of BTX‐A treatment. Future studies are needed to investigate the clinical application of this finding.

White-matter change in mesial temporal sclerosis : Correlation of MRI with PET, pathology, and clinical features

Summary: Purpose: To assess the magnetic resonance imaging (MRI), positron emission tomography (PET), pathology, and clinical findings of patients with the MRI feature of white‐matter change (WMC) in the anterior temporal lobe.

Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma

The prognosis for patients with recurrent glioblastomas (GBMs) is dismal, with a median survival of 3-6 months. We performed a phase II trial of low-dose continuous (metronomic) treatment using temozolomide (TMZ) for recurrent GBMs. TMZ-refractory patients with GBM who experienced disease recurrence or progression during or after the cyclic treatment schedule of TMZ after surgery and standard radiotherapy were eligible. This phase II trial included 2 cohorts of patients. The initial cohort, comprising 10 patients, received TMZ at 40 mg/m(2) everyday. After this regimen seemed safe and effective, the metronomic schedule was changed to 50 mg/m(2) everyday. The second cohort, comprising 28 patients, received TMZ at 50 mg/m(2) everyday. The 6-month progression-free survival in all 38 patients was 32.5% (95% CI: 29.3%-35.8%) and the 6-month overall survival was 56.0% (95% CI: 36.2%-75.8%). One patient developed a grade III neutropenia, grade II thrombocytopenia in 3 patients, and grade II increase of liver enzyme (GOT/GPT) in 3 patients. Of all patients included in this study, 4 patients were withdrawn from this study because of side effects including sustained hematological disorders, cryptococcal infection, and cellulitis. In a response group, quality of life measured with short form-36 was well preserved, when compared with the pretreatment status. Metronomic treatment of TMZ is an effective treatment for recurrent GBM that is even refractory to conventional treatment of TMZ and has acceptable toxicity.

Focal cortical dysplasia: comparison of MRI and FDG-PET.

PURPOSE The purpose of this work was to compare the use of MRI and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the diagnosis of focal cortical dysplasia (FCD). METHOD Nineteen patients with surgically proven FCD were analyzed retrospectively. MRI was performed in all patients, and FDG-PET was performed in 17 patients. We compared the MR and FDG-PET findings of FCD according to the histologic findings that were classified into three grades. RESULTS Four cases were classified as Grade I, 4 cases as Grade II, and 11 cases as Grade III FCD. The lesions were detected on MRI in 9 (82%) of the 11 patients with Grade III FCD and in only 1 (13%) of the 8 patients with Grade I and II FCD. Cortical hypometabolism of the lesion was revealed on FDG-PET in 6 (86%) of the 7 patients with Grade I and II FCD and in 9 (90%) of the 10 patients with Grade III FCD. The extent of the cortical abnormality was larger on FDG-PET than on MRI in 11 (65%) of the 17 patients. CONCLUSION FDG-PET is more useful in delineating the cortical abnormality in patients with mild degrees of FCD. The extent of the lesion was larger or similar on FDG-PET compared with that of the MRI.

Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma

Of the genetic changes in primary central nervous system lymphoma (PCNSL), little is known. To detect copy number alterations and differentially expressed genes in PCNSL, we analyzed a total of 12 PCNSL samples with high-resolution array-based comparative genomic hybridization and performed expression profiling in 7 of the 12 samples. The most frequent deletion found in 8 patients (66.7%) occurred in 9p21.3 containing CDKN2A. We compiled the top 96 genes (family-wise error rate, P < .05) showing the greatest differential expression between PCNSL and normal lymph node tissues. From these, we selected 8 candidate genes (NPFFR2, C4orf7, OSMR, EMCN, TPO, FNDC1, COL12A1, and MSC) in which expression changes were associated with copy number aberrations. All 8 genes showed both down-regulation in expression microarray and deletion in array-based comparative genomic hybridization analyses. These genes participate in cell signaling or cell adhesion. In addition, low mRNA expression of C4orf7 was significantly associated with poor survival (P = .0425). Using gene set enrichment analysis, we identified several signal transduction pathways, such as Janus kinase-signal transducers and activators of transcription pathway and adhesion-related pathways, which may be involved in pathogenesis of PCNSL. In conclusion, this study identified novel tumor suppressor genes that may serve as therapeutic targets of PCNSL.

Ultrastructural Changes of Mitochondria in the Skeletal Muscle of Patients with Amyotrophic Lateral Sclerosis

Functional defects and morphological changes of mitochondria have been reported to be in the skeletal muscle of patients with amyotrophic lateral sclerosis (ALS). Recent studies suggested that mitochondrial abnormalities are related to the pathogenesis of ALS. The purpose of this study is to evaluate the ultrastructural changes of muscle mitochondria in ALS patients. The authors examined 49 cases of diagnostic muscle biopsy samples with definite or probable ALS by electron microscopy. Of the 49 cases, 5 (10%) had ultrastructural abnormalities of muscle mitochondria, including giant mitochondria, paracrystalline inclusions, and abnormal cristae. These abnormal mitochondria were mainly observed among subsarcolemmal mitochondrial aggregates.

Thymic ultrasound. I. Intrathymic anatomy in infants

Background. The gross appearance and echogenicity of the normal thymus have been described, but specific intrathymic anatomy has not been evaluated with imaging. Subjects and methods. The thymus from a 34-week-gestation stillborn male was examined with ultrasound, and the images were correlated with microscopic findings. Thymic ultrasound was performed in 12 infants without any evidence of thymic abnormality, severe infection, or chronic illness. Images were evaluated focusing on intrathymic parenchymal anatomy and compared to the liver, spleen, and thyroid gland. Results. In the specimen thymus, ultrasound demonstrated connective-tissue septa as echogenic linear structures. The cortex was relatively hypoechoic, whereas the medulla was echogenic. The blood vessels within the septa were seen as discrete echoes. In vivo ultrasound demonstrated multiple branching echogenic linear structures and foci throughout the parenchyma, representing connective-tissue septa or blood vessels within the septa. The normal thymus was easily differentiated from the liver, spleen, and thyroid glands. Conclusion. Ultrasound is capable of demonstrating intrathymic anatomy, including the medulla, cortex, septa, and blood vessels in a fresh specimen. In vivo connective-tissue septa and blood vessels in the thymic parenchyma produce a unique echo pattern.