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.

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.

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.

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.

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.

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.