Monitoring rate and predictability of intraoperative monitoring in patients with intradural extramedullary and epidural metastatic spinal tumors.

STUDY DESIGN: Single-center retrospective study. OBJECTIVES: To evaluate the monitoring rate, sensitivity and specificity of intraoperative monitoring (IOM) during removal of intradural extramedullary (IDEM) or epidural metastatic spinal tumors. Also, to assess the efficacy of monitoring somatosensory-evoked potentials (SSEP) when motor-evoked potentials (MEP) are not measurable. SETTING: The Neuro-Oncology Clinic, National Cancer Center, Korea. METHODS: Patients (n=101) with IDEM or epidural metastatic spinal tumors at the cord level underwent surgeries monitored with SSEP and/or MEP. The monitoring rate was defined as negative when MEP or SSEP could not be measured after reversal of the neuromuscular block under general anesthesia. Positive IOM changes included more than a 50% change in the MEP or SSEP amplitude and more than a 10% delay in SSEP latency. RESULTS: MEP was measurable in 73% of patients. The MEP monitoring rate in patients with motor power grades of 3 or less was 39%, which was lower than that of SSEP (83%). The sensitivity, specificity and predictability of MEP for motor changes were 93, 90 and 91%, respectively. Conversely, the sensitivity, specificity and predictability of SSEP were 62, 97 and 89%, respectively. In patients in whom MEP was not measurable (n=24), SSEP was monitored with a predictability of 83%. CONCLUSION: In cases of extramedullary spinal tumors, MEP shows a higher sensitivity than SSEP does. However, the monitoring rate of MEP in non-ambulatory patients was lower than that of SSEP. In those cases, SSEP can be useful to monitor for postoperative neurological deficits.

Evaluation of the predictors of readmission in Korean patients with heart failure.

WHAT IS KNOWN AND OBJECTIVE: Various factors contribute to the high rate of readmission among patients hospitalized with heart failure (HF). Determination of these factors is fundamental to identify potential targets for intervention in hospitalized patients. METHODS: The retrospective cohort study used a large national insurance database to identify episodes of HF. Clinical information up to 12 months from the index hospitalization was obtained. Depending on their outcome, eligible patients were classified into a 30-day readmission group after discharge or a non-readmission group. Potential predictors of 30-day readmission were categorized by patient, drug therapy and health system utilization factors. RESULTS AND DISCUSSION: Heart failure was identified in 19 128 inpatients. Of these, 27·6% were readmitted within 30 days after discharge. The mean Charlson comorbidity index (CCI) score was 5·2 ± 2·9 for the readmission group and 4·3 ± 2·5 for the non-readmission group. The strongest predictors included paralysis [adjusted odds ratio (AOR) 2·27, 95% confidence interval (CI) 1·97-2·62], followed by metastatic cancer (AOR 2·22, 95% CI 1·81-2·72) and loop diuretic therapy (AOR 1·52, 95% CI 1·29-1·79). A prescription of ACE inhibitor or angiotensin receptor blocker at discharge was associated with a 17% decreased risk (AOR 0·83, 95% CI 0·77-0·89). WHAT IS NEW AND CONCLUSIONS: Hospitalized patients with HF have a 30-day all-cause readmission rate exceeding a quarter. Post-discharge care should focus on patients with advanced age, acuity of admission, enrolled medical aid, hospitalization exceeding 14 days, higher CCI score, more than 10 prescription drugs at discharge, presence of several comorbidities and loop diuretic therapy, which are independent predictors for 30-day readmission.

Impact of GATA4 variants on stable warfarin doses in patients with prosthetic heart valves.

Interindividual variability in stable warfarin doses is largely attributed to VKORC1 and CYP2C9 variants. On the basis of a recent finding of the role of GATA4 in control of CYP2C9 expression, we tested a possible effect of GATA4 genotypes on variability in warfarin response using 201 Korean patients with prosthetic cardiac valves. Two single-nucleotide polymorphisms (SNPs), rs2645400 (G>T) and rs4841588 (G>T), were significantly associated with stable warfarin doses in patients carrying CYP2C9 wild-type homozygotes; homozygote carriers of these two SNPs required higher doses than those with other genotypes (5.94±1.73 versus 5.34±1.88 mg, P=0.026; 5.94±1.66 versus 5.37±1.92, P=0.036, respectively). Multivariate analysis showed that two GATA4 combinations, rs867858 (G>T)/rs10090884 (A>C) and rs2645400 (G>T)/rs4841588 (G>T), increased contribution to the overall warfarin dose variability from 36.4 to 40.9%. This study revealed that GATA4 can be predictive of stable warfarin dose and extended warfarin pharmacogenetics further to the regulation of CYP2C9 expression.

Association of gene polymorphisms with the risk of warfarin bleeding complications at therapeutic INR in patients with mechanical cardiac valves.

WHAT IS KNOWN AND OBJECTIVE: Pharmacogenetic studies of the genetic regulation of warfarin dose requirement have been reported, but few have been on the bleeding complications at therapeutic international normalized ratio (INR). This study aimed to evaluate the effect of gene polymorphisms of CYP2C9, VKORC1, thrombomodulin (THBD) and C-reactive protein (CRP) on the risk of bleeding complications of warfarin at therapeutic INR in Korean patients with mechanical cardiac valves. METHODS: A retrospective warfarin pharmacogenetic association study was performed. One hundred and forty-two patients with mechanical cardiac valves who were on warfarin anticoagulation therapy and maintained INR levels of 2·0-3·0 for 3 consecutive time intervals were followed up. CYP2C9 rs1057910, VKORC1 rs9934438, CRP rs1205, THBD rs1042580 and THBD rs3176123 were genotyped. The association between genotypes and warfarin bleeding complications was evaluated using logistic regression analysis, adjusted for demographic and clinical factors. RESULTS AND DISCUSSION: Of 142 eligible patients, 21 patients (14·8%) had bleeding complications at therapeutic INR. Patients with the G allele in THBD rs1042580 (AG or GG) had a lower risk of bleeding than patients with the AA genotype (adjusted OR: 0·210, 95% CI: 0·050-0·875, P = 0·032). The THBD rs3176123 polymorphism did not show any association with bleeding. For CRP rs1205, patients with the A allele (GA or AA genotype) had a higher risk of bleeding than patients with the GG genotype (adjusted OR: 5·575, 95% CI: 1·409-22·058, P = 0·014). Variant VKORC1 and CYP2C9 genotypes did not confer a significant increase in the risk for bleeding complications. WHAT IS NEW AND CONCLUSIONS: As expected, no association could be found between bleeding complications and two dose-related genes (CYP2C9*3 and VKORC1 rs9934438). In contrast, our results suggest that two genetic markers (THBD rs1042580 and CRP rs1205) could be predictors of bleeding complications of warfarin at normal INR. Given the retrospective study design and the relatively small sample size, our hypothesis requires further independent validation using more robust prospective designs. However, additional retrospective studies similar to ours but in populations with different genetic backgrounds should also be useful.

NF-κB and STAT3 cooperatively induce IL6 in starved cancer cells.

A number of genes involved in tumorigenesis have been known to be controlled by signal transducer and activator of transcription 3 (STAT3) and NF-κB, either synergistically or individually. In starved cancer cells, we found that NF-κB was activated through endoplasmic reticulum stress signals, which depend on reactive oxygen species, cytosolic calcium and preserved translation of NF-κB p65 subunit, but independent of IκBα serine phosphorylation, thereby resulting in IL6 induction. STAT3 was required for proper induction of IL6 by NF-κB. They existed as identical nuclear complexes in proximal IL6 promoters, and STAT3 had critical roles in binding to IL6 promoters as well as nuclear retention of NF-κB. The conditioned media from starved cancer cells contained various secretory factors, such as IL6, IL9, VWF (von Willebrand factor), FREM1 (FRAS1 related extracellular matrix 1), SAA1 (serum amyloid A1), SDK1 (sidekick homolog 1) and ADAM12 (ADAM metallopeptidase domain 12), induced by NF-κB and STAT3 and promoted clonogenic capacities of cancer cells, and proliferation and migration of human umbilical vein endothelial cells. These results suggest novel survival strategies of cancer cells by which two oncogenic transcriptional factors, NF-κB and STAT3, are activated simultaneously by an intrinsic mechanism during stressful conditions of cancer cells, and they cooperatively induce various survival factors.

The sphingosine kinase activator K6PC-5 stimulates C2C12 myoblast differentiation.

Previously, K6PC-5, a synthetic derivative of ceramide, was demonstrated to activate sphingosine kinase (SK)-1 in keratinocytes. In this study its potential biological effect in mouse myoblasts was examined. The obtained results show that K6PC-5 promotes myogenic differentiation by enhancing myogenic marker expression, differentiation index and fusion index. Interestingly, its biological action was prevented by pharmacological inhibition of SK or S1P2 receptor, in full agreement with their recognized role in myoblast differentiation. This is the first evidence that pharmacological activation of SK accelerates myogenesis and suggests that this new therapeutic strategy could be possibly employed in skeletal muscle disorders where muscle regeneration is deficient.

Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas.

Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the post-transcriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas.

Comparison of bioavailability of two ubidecarenone products in healthy Korean volunteers.

OBJECTIVE: This study aimed to evaluate the bioavailability of two pharmaceutical products of ubidecarenone (coenzyme Q10, CoQ10). MATERIALS: Two brands (brand A and brand B) of commercial CoQ10 hard capsules. METHODS: Two brands of CoQ10 capsules were administered at 100 mg dose to two groups of healthy volunteers, respectively, and blood samples were withdrawn at predetermined time intervals and assayed by a validated HPLC method with an electrochemical detector. RESULTS AND CONCLUSIONS: Intra- and inter-day precision and inter-day accuracy were acceptable for all quality control samples including the lower limit of quantitation of 50 ng/ml. Recovery of CoQ10 from human plasma was greater than 98.2%. CoQ10 was stable in human plasma under various storage conditions. This method was applied to a pharmacokinetic study after oral administration of CoQ10 hard capsules to healthy volunteers. The intrinsic CoQ10 concentrations were measured for three consecutive days before drug administration, which were ranged between 0.68 and 0.79 microg/ml, and there was no statistically significant difference between groups. In brand A, the plasma concentration after administration of CoQ10 was not higher than the intrinsic level, indicating that no significant drug absorption occurred, whereas considerably higher concentrations were obtained with brand B. The dissolution rates of brand A and B after 3 h were 0.35 +/- 0.09 and 1.27 +/- 0.16%, respectively. From the adjusted concentration-time curve, the AUC and t1/2 of brand B were calculated to be 11.51 +/- 5.76 microg x h/ml and 21.7 h, respectively. A mean Cmax of 0.32 +/- 0.1 microg/ml was obtained at 7.9 h. In conclusion, it was found that bioavailability of CoQ10 was significantly different depending on the formulations, and dissolution could be one of the important factors affecting CoQ10 absorption.

Usefulness of (18)F-fluorodeoxyglucose PET for radiosurgery planning and response monitoring in patients with recurrent spinal metastasis.

INTRODUCTION: With the advancement and successful treatment of metastatic spinal cord disease, newer treatments are needed for the long-term survivors of recurrent disease. The lack of a standardized re-treatment regimen and the difficulty in delineating the tumor margins among patients who have received the treatment with metallic spinal fixation and conventional radiation are two of the challenges to be faced in recurrent metastatic spinal cord disease. In these patients, we applied hypofractionated stereotactic radiosurgery by defining the tumor margin with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). PATIENTS AND METHODS: Three consecutive recurrent spinal metastasis patients underwent the CyberKnife treatment (Accuray, Inc., Sunnyvale, CA) from March 2004 to July 2004. A three-fraction schedule was applied at approximately 24 hour intervals. One patient had sarcoma and the other two patients had breast cancer. All patients had received previous conventional radiotherapy after operation ranging from 30 Gy to 45 Gy. CT-based planning was corrected by the FDG-PET hyperuptake area with the help of nuclear medicine. The mass responses were followed not only by MRI but also by FDG-PET, which was taken prior to treatment, and at one and six months after the treatment. The changes in standard uptake value (SUV) of serial PET were taken as a measure of response. To evaluate the relative SUV changes from different pretreatment values, we set a reduction index (RI), which represents the ratio of SUV change to pretreatment SUV. RESULTS: No significant complications were noted during treatment with a mean follow-up of 13.3 months. The tumor volume on CT-based planning was 2.2 times larger than that of the CT-PET combined planning in case 1 of paraspinal muscle invasion. But the tumor volumes showed minimal changes in the other cases, in which the metastatic tumors were confined to the vertebral bodies. The SUV one month after treatment showed variable decreases and the RI ranged from 0.07 to 0.7. However, the SUVs at 6 months were well correlated with the clinical results. One patient showed marginal failure and the other two patients showed local control of the tumor, as their RI values were 0.65 and 0.87, respectively. CONCLUSION: To our knowledge, this is the first report using FDG-PET with radiosurgery in patients with recurrent spinal metastases hidden under metallic artifacts. The mass responses measured by SUV changes in FDG-PET correlated with the clinical results.

Analgesic effects of intra-nasal enkephalins.

The analgesic effects of intranasal delivery of leucine enkephalin (Leu-Enk) and its synthetic analogue [D-ala(2)]-leucine enkephalinamide (YAGFL) with or without enzyme inhibitors and/or absorption enhancers were investigated using the acetic acid-induced writhing test in mice. The analgesic activity was significantly affected by the time delay after the administration of Leu-Enk; the inhibition rates for the groups administered with acetic acid 5 min and 30 min after the administration of Leu-Enk were 56.40 +/- 8.54 and 17.98 +/- 7.07%, respectively. The addition of enzyme inhibitors and absorption enhancers markedly increased the inhibition rate of Leu-Enk and YAGFL; their inhibition rates were about four times and twice those without any enzyme inhibitor or absorption enhancer, respectively. The enzyme inhibitors and absorption enhancers that produced the highest inhibition rates of Leu-Enk and YAGFL were azelaic acid (1%), thimerosal (0.5 mM, TM), ethylenediamine-tetraacetic acid (5 mM, EDTA) and L-alpha-lysophosphatidylcholine (0.5%, LPC), and TM (0.5 mM), EDTA (5 mM), LPC (0.5%) and povidone (5%), respectively. The ED50 value of both enkephalins was also determined and found to be about 13 microg kg(-1), which is 850 and 60 times more potent than literature values for ketoprofen and morphine, respectively. Based on these results it was concluded that Leu-Enk or YAGFL could exert very high analgesic activity when administered nasally with a combination of inhibitors and absorption enhancers as compared with other analgesics.

Postoperative spinal seeding of craniopharyngioma. Case report.

The authors present a case of postoperative spinal seeding of papillary craniopharyngioma. This 27-year-old man who had previously undergone subtotal removal of a suprasellar craniopharyngioma was admitted because of low-back and right leg pain. Results of neurological examination showed a limitation in straight-leg raising in the right side with no sensorimotor changes. Magnetic resonance imaging of the lumbar spine demonstrated multiple enhanced intradural extramedullary masses causing spinal cord compression. Pathological examination of the tumor tissue obtained via laminectomy revealed papillary craniopharyngioma, which had the same histological features as those of the previous suprasellar tumor. Several ectopic recurrences of craniopharyngioma have been reported; however, the authors believe that this is the first published report of the spinal seeding of craniopharyngioma.

A cranio-orbital-zygomatic approach to dumbbell-shaped trigeminal neurinomas using the petrous window.

We applied a cranio-orbital-zygomatic approach that extends the temporal craniotomy more posteriorly and minimizes the frontal orbitotomy of an ordinary orbitozygomatic approach in order to provide wide access to the already eroded petrous apices along the long axis of trigeminal neurinomas. We treated seven dumbbell-shaped trigeminal neurinomas between 1991 and 1998 (mean follow-up, 38 months; range, 9 to 109 months). The configuration of the tumor mass was assessed on magnetic resonance imaging by measuring its long diameter in the middle and posterior fossae and the width of petrous erosion. Tumors were then classified into five types based on their distribution over the petrous ridge. Total removal was achieved in six patients, who showed no evidence of tumor recurrence during the follow-up period. The only major complication was one case of anesthesia dolorosa. The one patient with a subtotal removal developed a recurrence 12 months after surgery, in the posterior fossa. The cranioorbital-zygomatic approach could be an effective method for removing dumbbell-shaped trigeminal neurinomas, particularly in cases of wide petrous erosion from the tumor. If, however, the tumor has a larger posterior fossa component, this approach may not provide adequate exposure to achieve a total resection.

Effect of vehicles and enhancers on the in vitro skin penetration of aspalatone and its enzymatic degradation across rat skins.

The feasibility of skin penetration was studied for aspalatone (AM, acetylsalicylic acid maltol ester), a novel antithrombotic agent. In this study, hairless mouse dorsal skins were used as a model to select composition of vehicle and AM. Based on measurements of solubility and partition coefficient, the concentration of PG that showed the highest flux for AM across the hairless mouse skin was found to be 40%. The cumulative amount permeated at 48 h, however, appear inadequate, even when the PG concentration was employed. To identify a suitable absorption enhancer and its optimal concentration for AM, a number of absorption enhancers and a variety of concentration were screened for the increase in transdermal flux of AM. Amongst these, linoleic acid (LOA) at the concentration of 5% was found to have the largest enhancement factor (i.e., 132). However, a further increase in AM flux was not found in the fatty acid concentration greater than 5%, indicating the enhancement effect is in a bell-shaped curve. In a study of the effect of AM concentration on the permeation, there was no difference in the permeation rate between 0.5 and 1% for AM, below its saturated concentration. At the donor concentration of 2%, over the saturated condition, the flux of AM was markedly increased. A considerable degradation of AM was found during permeation studies, and the extent was correlated with protein concentrations in the epidermal and serosal extracts, and skin homogenates. In rat dorsal skins, the protein concentration decreased in the rank order of skin homogenate > serosal extract > epidermal extract. Estimated first order degradation rate constants were 6.1 5 +/- 0.14, 0.57 +/- 0.02 and 0.011 +/- 0.004 h(-1) for skin homogenate, serosal extract and epidermal extract, respectively. Therefore, it appeared that AM was hydrolyzed to some extent into salicylmaltol by esterases in the dermal and subcutaneous tissues of skin. Taken together, our data indicated that transdermal delivery of AM is feasible when the combination of PG and LOA is used as a vehicle. However, since AM is not metabolically stable, acceptable degradation inhibitors may be necessary to fully realize the transdermal delivery of the drug.

In vitro percutaneous absorption of tenoxicam from pressure-sensitive adhesive matrices across the hairless mouse skin.

To investigate the feasibility of developing a new tenoxicam plaster, the effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from a pressure-sensitive adhesive (PSA) matrices across the dorsal hairless mouse skin were studied. Vehicles employed in this study were propylene glycol (PG)-oleyl alcohol (OAI), PG-oleic acid (OA), and diethylene glycol monoethyl ether (DGME)-propylene glycol monolaurate (PGML) cosolvents with/without fatty acids. In this study, amines such as triethanolamine (TEA) and tromethamine (TM) were additionally used as a solubilizer. Among PSAs used, Duro-Tak 87-2510 showed much higher release rate than either Duro-Tak 87-2100 or Duro-Tak 87-2196. The relatively high flux rate was obtained with the formulation of DGME-PGML (40:60, v/v) with 3% OA and 5% TM, and the flux increased as a function of the dose; the initial flux up to 12 h was 4.98 +/- 1.38 microg/cm2/h at the tenoxicam dose of 50 mg/70 cm2. This flux was much higher than that of a commercial piroxicam patch (Trast) (1.24 +/- 0.73 microg/ cm2/hr) with almost only one-third that of the commercial patch. Therefore, these observations indicated that these composition of tenoxicam plaster may be practically applicable.

Meningioma manifesting intracerebral haemorrhage: a possible mechanism of haemorrhage.

We present a possible mechanism of intracerebral peritumoural haemorrhage in meningioma based on the clinical data of three of our cases. A meningioma manifesting intracerebral haemorrhage is uncommon and some sporadic case reports have been presented, but without any proven mechanisms. We are presenting three cases of convexity meningioma manifesting spontaneous intracerebral haemorrhage with apoplectiform onset. All three patients had no evidence of bleeding tendency or other predisposing factors for haemorrhage. Preoperative radiological studies showed a solid mass attached to the dura with intracerebral peritumoural haematoma. Total removal of the tumour and haematoma could be achieved in every case. Histological investigation revealed extensive tumour infarction in two cases and fibrosis related to pre-existing ischaemia in the other case. The diagnoses were atypical meningioma in two cases and transitional type in one case. We suggest that extensive tumour infarction might be a cause of spontaneous intracerebral peritumoural haemorrhage in our series of patients.

Gamma knife radiosurgery for brain metastases: prognostic factors for survival and local control.

OBJECT: The authors conducted an analysis of prognostic factors for patient survival and local control of brain metastases after gamma knife radiosurgery. METHODS: In the survival analysis, 53 consecutive patients with 121 lesions treated in the last 2 years were examined. Common primary sites were lung (26 patients), kidney (seven), breast (three), and colon (three). Patient age ranged from 28 to 75 years (median 58 years) and the female/male ratio was 1:0.9. The median tumor volume was 2.1 cm3 (range 0.02-45.5 cm3) and the average prescription dose was 15.4 Gy to the 50% isodose. The median follow up was 12 months (range 1-23 months) and the median survival was 46 weeks. Six-month and 1-year survival rates were 63% and 39%, respectively. Karnofsky Performance Scale score, tumor volume, and presence of extracranial disease were statistically significant prognostic factors (p < 0.05) for survival in multivariate analysis. Number of lesions, patient age, and adjuvant whole-brain radiation therapy were not statistically significant. Ninety-one of 121 lesions with follow-up images were included in the local control analysis. The 1-year actuarial local control rate was 48%. In multivariate analysis smaller volume was associated with better control (p = 0.0043), and, control period of renal cell carcinoma was shorter than that of the other tumor types (p = 0.0070). CONCLUSIONS: Karnofsky Performance Scale score, tumor volume, controlled primary cancer, and absence of extracranial metastases were associated with longer survival in the present study. For local control, tumor volume was a statistically significant factor.

Aneurysm at the origin of accessory middle cerebral artery associated with middle cerebral artery aplasia: case report.

A case of ruptured aneurysm at the origin of accessory middle cerebral artery associated with ipsilateral middle cerebral artery aplasia is reported. The angiograms did not show a middle cerebral artery shadow on the lesion side. Instead, the accessory middle cerebral artery ran toward the Sylvian fissure and supplied the middle cerebral artery territory along with multiple hypertrophied perforating branches. The operative findings confirmed that the cord-like, rudimentary middle cerebral artery had no internal blood flow. The effect of these combined anomalies on the hemodynamic equilibrium between the arteries of the same embryologic trees and the genesis of aneurysm is worthy of notice.