Clinical, histopathological, and molecular analyses of IDH-wild-type WHO grade II-III gliomas to establish genetic predictors of poor prognosis.

The genetic features of isocitrate dehydrogenase-wild-type (IDH-wt) lower-grade gliomas (LGGs; World Health Organization grades II and III) are not well defined. This study analyzed the genetic and other features of IDH-wt LGGs to develop a subclassification that can be used to predict their prognosis. Clinical, histopathological, and genetic features of 35 cases of diffuse IDH-wt astrocytoma and IDH-wt anaplastic astrocytoma were analyzed. The following genetic factors were examined: mutations of B-rapidly accelerated fibrosarcoma, telomerase reverse transcriptase promoter (TERTp), histone 3 family 3A, and alpha-thalassemia/mental retardation syndrome, X-linked; and copy number aberrations. In the univariate analysis, the following factors were associated with poor overall survival (OS): the histopathological diagnosis, TERTp mutation, the gain of chromosome 7 (+ 7), and the loss of chromosome 10q (- 10q). In the multivariate analysis, + 7, - 10q, and TERTp mutation were independent prognostic factors associated with poor OS. The median OS was significantly worse for patients who harbored at least one of these factors than for those without any of them (18.5 vs. 54.5 months, P = 0.002). The subclassification of IDH-wt LGGs according to the genetic factors + 7, - 10q, and TERTp mutation is potentially useful for predicting the prognosis.

Delayed neurological deterioration following atlantoaxial facet joint distraction and fixation in a patient with Chiari malformation type I.

Chiari malformation type I (CM-I) is typically treated with foramen magnum decompression. However, a recent study proposed a new technique for patients with CM-I, wherein only short atlantoaxial joint fusion and distraction is applied. Posterior fusion with or without atlantoaxial distraction is a potential option for patients with CM-I associated with basilar invagination or complex anomalous bony craniovertebral junction pathology, since this procedure allows clinicians to avoid using the technically demanding transoral approach in which some or all of the odontoid tip is invisible. Distraction of the atlantoaxial joint reduces ventral cervicomedullary compression, leading to neurological improvement. Here, the authors report the case of a 50-year-old woman with CM-I plus basilar invagination whose condition immediately improved but then gradually deteriorated following atlantoaxial joint distraction and fusion. Therefore, the authors performed endonasal/transoral odontoidectomy, which resulted in prolonged neurological recovery. Short atlantoaxial fusion with distraction is a smart and ideal surgical planning concept that can result in significant neurological improvement. However, this case suggests that anterior odontoidectomy is still an essential element of the intervention strategy for patients with CM-I with complex craniovertebral junction pathology.

Potent apoptosis-inducing activity of erypoegin K, an isoflavone isolated from Erythrina poeppigiana, against human leukemia HL-60 cells.

Erypoegin K is an isoflavone isolated from the stem bark of Erythrina poeppigiana. It contains a furan group at the A-ring of the core isoflavone structure and can inhibit the activity of glyoxalase I, an enzyme that catalyzes the detoxification of methylglyoxal (MG), a by-product of glycolysis. In the present study, we found that erypoegin K has a potent cytotoxic effect on human leukemia HL-60 cells. Its cytotoxic effect was much stronger than that of a known glyoxalase I inhibitor S-p-bromobenzylglutathione cyclopentyl diester. Conversely, erypoegin K demonstrated weak cytotoxicity toward normal human peripheral lymphocytes. The treatment of HL-60 cells with erypoegin K significantly induced caspase-3 activity, whereas the pretreatment of the cells with caspase-3 inhibitor suppressed erypoegin K-induced cell death. Furthermore, nuclear condensation and apoptotic genome DNA fragmentation were observed in erypoegin K-treated HL-60 cells. These results indicated that the observed cell death was mediated by apoptosis. In addition, the toxic compound MG was highly accumulated in the culture medium of erypoegin K-treated HL-60 cells, suggesting that cell apoptosis was triggered by extracellular MG. The present study showed that erypoegin K has a potent apoptosis-inducing effect on cancerous cell lines, such as HL-60.

World Health Organization grade II-III astrocytomas consist of genetically distinct tumor lineages.

Recent investigations revealed genetic analysis provides important information in management of gliomas, and we previously reported grade II-III gliomas could be classified into clinically relevant subgroups based on the DNA copy number aberrations (CNAs). To develop more precise genetic subgrouping, we investigated the correlation between CNAs and mutational status of the gene encoding isocitrate dehydrogenase (IDH) of those tumors. We analyzed the IDH status and CNAs of 174 adult supratentorial gliomas of astrocytic or oligodendroglial origin by PCR-based direct sequencing and comparative genomic hybridization, respectively. We analyzed the relationship between genetic subclassification and clinical features. We found the most frequent aberrations in IDH mutant tumors were the combined whole arm-loss of 1p and 19q (1p/19q codeletion) followed by gain on chromosome arm 7q (+7q). The gain of whole chromosome 7 (+7) and loss of 10q (-10q) were detected in IDH wild-type tumors. Kaplan-Meier estimates for progression-free survival showed that the tumors with mutant IDH, -1p/19q, or +7q (in the absence of +7p) survived longer than tumors with wild-type IDH, +7, or -10q. As tumors with +7 (IDH wild-type) showed a more aggressive clinical nature, they are probably not a subtype that developed from the slowly progressive tumors with +7q (IDH mutant). Thus, tumors with a gain on chromosome 7 (mostly astrocytic) comprise multiple lineages, and such differences in their biological nature should be taken into consideration during their clinical management.

Warfarin-associated Intraspinal Hematoma.

Intracerebral hemorrhage is a well-known complication resulting from warfarin use; however, warfarin-associated intraspinal hematoma is very rare. Warfarin-associated intraspinal hematoma may exhibit delayed progression, and patients may present with atypical symptoms, occasionally resulting in delayed diagnosis. We report the case of a 65-year-old man who visited our emergency department (ED) with acute urinary retention. He had been previously diagnosed with non-valvular atrial fibrillation, arterial hypertension, and benign prostatic hyperplasia, and he used warfarin for the prevention of systemic embolism. The patient was initially diagnosed with worsening of the prostatic hyperplasia. After 2 days, he revisited the ED with painless paraparesis. Magnetic resonance imaging of the thoracic spine revealed an intraspinal hematoma at Th7-8, and blood coagulation tests indicated a prothrombin time-international normalized ratio of 3.33. Despite attempts to reverse the effects of warfarin with vitamin K administration, the paraparesis progressed to paraplegia, necessitating urgent surgical removal of the hematoma. Partial recovery of motor function was evident after surgery. From the present case, we learned that intraspinal hematoma should be included in the differential diagnosis of patients using warfarin who present with acute urinary retention. Although there are no evidence-based treatment guidelines for warfarin-associated intraspinal hematoma, surgical treatment may be warranted for those who exhibit neurological deterioration.

Application of time-spatial labeling inversion pulse magnetic resonance imaging in the diagnosis of spontaneous intracranial hypotension due to high-flow cerebrospinal fluid leakage at C1-2.

BACKGROUND: Spontaneous intracranial hypotension (SIH) due to cerebrospinal fluid (CSF) leakage at C1-2 poses diagnostic and therapeutic challenges to spine surgeons. Although computed tomography (CT) myelography has been the diagnostic imaging modality of choice for identifying the CSF leakage point, extradural CSF collection at C1-2 on conventional CT myelography or magnetic resonance imaging (MRI) may often be a false localizing sign. CASE DESCRIPTION: The present study reports the successful application of time-spatial labeling inversion pulse (T-SLIP) MRI, which enabled the precise identification of the CSF leakage point at C1-2 in a 28-year-old woman with intractable SIH. After identifying the leakage point using both CT myelography and T-SLIP MRI, surgery was performed to seal the CSF leak. Intraoperatively, a pouch suggestive of an extradural arachnoid cyst around the left C2 nerve root was found, which was repaired by packing the pouch with muscle and fibrin glue. Clinical improvement was observed shortly after surgery, and postoperative imaging revealed the disappearance of the CSF leakage. CONCLUSIONS: T-SLIP MRI may provide useful information on the flow dynamics of CSF in SIH patients due to high-flow leakage. However, further experience is required to assess its sensitivity and specificity as an imaging modality for identifying CSF leakage points.

PCR-Based Simple Subgrouping Is Validated for Classification of Gliomas and Defines Negative Prognostic Copy Number Aberrations in IDH Mutant Gliomas.

Genetic subgrouping of gliomas has been emphasized recently, particularly after the finding of isocitrate dehydrogenase 1 (IDH1) mutations. In a previous study, we investigated whole-chromosome copy number aberrations (CNAs) of gliomas and have described genetic subgrouping based on CNAs and IDH1 mutations. Subsequently, we classified gliomas using simple polymerase chain reaction (PCR)-based methods to improve the availability of genetic subgrouping. We selected IDH1/2 and TP53 as markers and analyzed 237 adult supratentorial gliomas using Sanger sequencing. Using these markers, we classified gliomas into three subgroups that were strongly associated with patient prognoses. These included IDH mutant gliomas without TP53 mutations, IDH mutant gliomas with TP53 mutations, and IDH wild-type gliomas. IDH mutant gliomas without TP53 mutations, which mostly corresponded to gliomas carrying 1p19q co-deletions, showed lower recurrence rates than the other 2 groups. In the other high-recurrence groups, the median progression-free survival (PFS) and overall survival (OS) of patients with IDH mutant gliomas with TP53 mutations were significantly longer than those of patients with IDH wild-type gliomas. Notably, most IDH mutant gliomas with TP53 mutations had at least one of the CNAs +7q, +8q, -9p, and -11p. Moreover, IDH mutant gliomas with at least one of these CNAs had a significantly worse prognosis than did other IDH mutant gliomas. PCR-based mutation analyses of IDH and TP53 were sufficient for simple genetic diagnosis of glioma that were strongly associated with prognosis of patients and enabled us to detect negative CNAs in IDH mutant gliomas.

Cardiopulmonary Resuscitation-induced Thoracic Vertebral Fracture: A Case Report.

Thoracic vertebral fractures are very unusual complications of cardiopulmonary resuscitation (CPR). A 78-year-old man developed cardiac arrest after aspirating and conventional CPR was performed. After recovery, the patient had complete paraplegia (Frankel grade A). Magnetic resonance image of spine showed a dislocation fracture with hematoma at T6 thoracic level. Computed tomography scan of chest revealed the fracture of sternum. After the patient's condition became stable with subsequent medical treatment, posterior decompression and pedicle screw fixation was performed. The patient had uneventful postoperative course with continued rehabilitation. Thus, this report emphasizes that care should be taken especially in elderly patients with fragile bone to recognize such rare complication of chest compression; however, adequate compressions to ensure circulation should be maintained.

Subgrouping of gliomas on the basis of genetic profiles.

Management of gliomas depends on histological diagnosis; there are, however, limitations to the systems presently used. Tumors in the same entity can have different clinical courses, especially when they are diagnosed as WHO grade II-III. Previous studies revealed that genetic subgrouping of gliomas provides useful information that could help establishment of treatment procedures on the basis of the genetic background of the tumors. Recently, the authors analyzed the chromosomal copy number aberrations (CNAs) of adult supratentorial gliomas by comparative genomic hybridization using microdissected tissue sections. The tumors were classified into subgroups according to chromosomal CNAs. WHO grade II-III gliomas contained a variety of genetic subgroups that correlated well with the clinical course. Of these, long progression-free survival was observed for tumors with +7q and those with -1p/19q, low-grade tumors of 2 major lineages, and, in our preliminary data, both were closely correlated with mutation of IDH1. Furthermore, in contrast with +7q tumors, the great majority of +7 or +7/-10q groups had wildtype IDH1. Genetic studies suggest that cytogenetic characterization may provide an additional classification system for gliomas, and new criteria could help to establish rational and objective means for analysis of treatment procedures.

Early seizures after clipping of unruptured aneurysms of the anterior circulation: analysis on consecutive 1,000 cases.

Seizures occurring after clipping of unruptured cerebral aneurysms have rarely been documented in the literature. The objective of this retrospective study is to clarify whether the frequency of early seizures, i.e., seizures occurring within 14 days of surgery, is influenced by patient- or aneurysm-specific characteristics. Data on 1,000 consecutive patients who underwent clipping of unruptured anterior circulation aneurysms were reviewed. They consisted of 387 men and 613 women with mean age of 59.8 ± 9.7 years. Fifty-one patients (5.1 %) developed early seizures. Interestingly, the frequency was similar to that occurring after clipping of unruptured posterior circulation aneurysms (n = 20, 5.0 %). Multivariate regression analysis revealed that younger age was correlated with early seizures (odds ratio (OR) 0.902; 95 % confidence interval (CI) 0.891-0.989). However, other variables, including aneurysm size and operation length, were not correlated. Although patients with history of epilepsy exhibited relatively high frequency of early seizures, the difference was not statistically significant. The frequency was unaffected by location or multiplicity of aneurysms. Thirty-one patients (61 %) developed seizures within 24 h of clipping. Regarding seizure types, 34 (67 %) developed generalized seizures and the other 17 (33 %) experienced partial seizures. Patients with generalized seizures were significantly more likely to harbor an iatrogenic brain lesion than those with partial seizures (47 vs. 18 %; OR 4.148; 95 % CI 1.005-17.113). Among 40 patients with follow-up period >12 months, seizures were temporary without recurrence in 38 (95 %). Although early seizures are mostly benign, a small possibility of them becoming a permanent morbidity needs to be explained to patients undergoing elective clipping.

Association between elevated plasma norepinephrine levels and cardiac wall motion abnormality in poor-grade subarachnoid hemorrhage patients.

Patients with aneurysmal subarachnoid hemorrhage (SAH) are frequently complicated by acute cardiac dysfunctions, including cardiac wall motion abnormality (WMA). Massive release of catecholamine into the systemic circulation after aneurysmal rupture is believed to result in WMA, and poor-grade SAH seems to be the most important risk factor. However, plasma catecholamine levels have rarely been measured in SAH patients with WMA, and previous studies indicated that the elevated levels might not necessarily predict WMA. The objective of this study is (1) to evaluate relationship between WMA and plasma catecholamine levels in poor-grade SAH patients in the acute phase and (2) to clarify clinical characteristics of SAH patients with WMA. Among 142 poor-grade (World Federation of Neurosurgical Societies grades IV and V) SAH patients, 48 underwent both transthoracic ultrasound and measurement of plasma catecholamine levels within 24 h of SAH onset. They were divided into WMA+ (n = 23) and WMA- (n = 25) groups, and intergroup comparison was made on demographics, plasma catecholamine levels, and outcomes. Plasma norepinephrine levels were significantly higher in WMA+ group than in WMA- group (2,098.4 ± 1,773.4 vs. 962.9 ± 838.9 pg/mL, p = 0.02), and the former showed significantly worse outcomes 90 days after admission. There were no intergroup differences in the plasma levels of epinephrine. Plasma norepinephrine levels were inversely correlated with left ventricular ejection fraction. Multivariate logistic regression analysis revealed that increased plasma norepinephrine levels were predictive of WMA, although age, female sex, and grade V SAH were not. This retrospective study highlights the role of norepinephrine in pathogenesis of SAH-induced WMA.

Detection of pulsation in ruptured and unruptured cerebral aneurysms by electrocardiographically gated 3-dimensional computed tomographic angiography with a 320-row area detector computed tomography and evaluation of its clinical usefulness.

BACKGROUND: In ruptured cerebral aneurysms (RCAs), identification of the rupture point of a cerebral aneurysm is useful for treatment planning. In unruptured cerebral aneurysms (URCAs), detection of the risk of aneurysmal rupture is also useful for patient management. OBJECTIVE: Electrocardiographic (ECG)-gated 3D-CT angiography was performed for patients with RCAs and URCAs using 320-row area detector CT (ADCT) to detect pulsation of the cerebral aneurysms. The clinical usefulness of this method was then evaluated. METHODS: Twelve patients had 12 RCAs, and 39 patients had 53 URCAs. A 320-row ADCT system was used to scan. ECG-gated reconstruction was then performed with the R-R interval divided into 20 phases. RESULTS: Pulsation was observed in 10 of the 12 RCAs. The bleeding site was considered to correspond to the area of pulsation. Pulsation was observed in 14 of 53 URCAs. Thirteen patients with 18 URCAs were followed. Of the 11 URCAs in which pulsation was not observed, 1 showed a change in shape. Of the 7 URCAs in which pulsation was observed, 3 showed a change in shape. URCAs in which pulsation was observed were more likely to show a change in shape (P = .082). CONCLUSION: The area of pulsation was found to correspond to the bleeding site in many RCAs. This information would be extremely useful for treatment planning. The detection of pulsation in an URCA is therefore considered to provide useful information for patient management.