Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations.

BACKGROUND: Accumulating evidence indicates that cancer stem cells (CSCs) drive tumorigenesis. This suggests that CSCs should make ideal therapeutic targets. However, because CSC populations in tumors appear heterogeneous, it remains unclear how CSCs might be effectively targeted. To investigate the mechanisms by which CSC populations maintain heterogeneity during self-renewal, we established a glioma sphere (GS) forming model, to generate a population in which glioma stem cells (GSCs) become enriched. We hypothesized, based on the clonal evolution concept, that with each passage in culture, heterogeneous clonal sublines of GSs are generated that progressively show increased proliferative ability. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we determined whether, with each passage, glioma neurosphere culture generated from four different glioma cell lines become progressively proliferative (i.e., enriched in large spheres). Rather than monitoring self-renewal, we measured heterogeneity based on neurosphere clone sizes (#cells/clone). Log-log plots of distributions of clone sizes yielded a good fit (r>0.90) to a straight line (log(% total clones) = k*log(#cells/clone)) indicating that the system follows a power-law (y = xk) with a specific degree exponent (k = -1.42). Repeated passaging of the total GS population showed that the same power-law was maintained over six passages (CV = -1.01 to -1.17). Surprisingly, passage of either isolated small or large subclones generated fully heterogeneous populations that retained the original power-law-dependent heterogeneity. The anti-GSC agent Temozolomide, which is well known as a standard therapy for glioblastoma multiforme (GBM), suppressed the self-renewal of clones, but it never disrupted the power-law behavior of a GS population. CONCLUSIONS/SIGNIFICANCE: Although the data above did not support the stated hypothesis, they did strongly suggest a novel mechanism that underlies CSC heterogeneity. They indicate that power-law growth governs the self-renewal of heterogeneous glioma stem cell populations. That the data always fit a power-law suggests that: (i) clone sizes follow continuous, non-random, and scale-free hierarchy; (ii) precise biologic rules that reflect self-organizing emergent behaviors govern the generation of neurospheres. That the power-law behavior and the original GS heterogeneity are maintained over multiple passages indicates that these rules are invariant. These self-organizing mechanisms very likely underlie tumor heterogeneity during tumor growth. Discovery of this power-law behavior provides a mechanism that could be targeted in the development of new, more effective, anti-cancer agents.

Neuroendoscopic biopsy and the treatment of tumor-associated hydrocephalus of the ventricular and paraventricular region in pediatric patients: a nationwide study in Japan.

A neuroendoscopic biopsy is a minimally invasive and useful procedure for the diagnosis and initial management of tumor-associated hydrocephalus. We describe the nationwide investigation of the current status of neuroendoscopic biopsy for intra- and paraventricular tumors in children, as well as the treatment of tumor-associated hydrocephalus in pediatric patients. The main items examined included the patient's age and sex, location of the tumor, pathological diagnosis, complications, treatment and efficacy of treatment of the tumor-associated hydrocephalus, and the dissemination during the postoperative course. Two hundred twenty-one pediatric patients (mean 8.6 years) from 67 institutions were registered. Endoscopic tumor biopsies were performed in 206 patients (93.2 %), and a histopathological diagnosis could be performed in 195 of these 206 patients (94.7 %). The most frequently histopathologically diagnosed tumor was a germ cell tumor (41.5 %), followed by astrocytic tumors (24.1 %) and cystic lesions (15.9 %). Associated hydrocephalus was observed in 177 patients (80.1 %), 101 of whom underwent endoscopic third ventriculostomy (ETV). The efficacy rate of the ETV in the perioperative period was 99.0 %, and the long-term response rate was 90.1 %. Perioperative complications other than fever were found in 24 patients (10.9 %). In the statistical analysis, pediatric long-term response rate to ETV (p = 0.025) showed significantly more favorable results for pediatric than adult patients (p < 0.05). Neuroendoscopic procedures involving pediatric intra- and paraventricular tumors were considered to be very useful, with a low incidence of complication, and were associated with higher safety.

[Neuroendoscopic surgery for intra- and para-ventricular tumors:impacts on biopsy and hydrocephalus treatment].

In this report, the authors retrospectively review and discuss their results for neuroendoscopic surgery for intra- and para-ventricular tumors. This study included 28 patients who were admitted to our hospital for intra- or para-ventricular tumors between January 2005 and March 2013. There were 17 males and 11 females, and their age varied widely from 1 to 75 years. Using a neuroendoscopic technique, tumor biopsy was attempted in all 28 patients. Biopsy was possible in 25 patients(89.3%)but not in the other 3(10.7%)because of hypervascularity or tumor bleeding. Of these 25 patients, pathological diagnosis was possible in 23(92%), but not in other 2(8%)because of incomplete sampling. In 18 of 28 patients, various forms of hydrocephalus were observed. Neuroendoscopic procedures were quite useful to improve cerebrospinal fluid dynamics in 13 of these patients, including endoscopic third ventriculostomy(ETV)in 9(except for 1 patient with ETV failure), septostomy with ventriculoperitoneal shunting(VPS)in 3, and cystostomy in 1. Simple VPS was performed in the other 4 patients. These results suggest that neuroendoscopic surgery is valuable as a minimally invasive procedure for pathological diagnosis and hydrocephalus treatments in patients with intra- and para-ventricular tumors. Further development of neuroendoscopic equipment is warranted to accurately diagnose tumors with hypervascularity and subependymal tumors.

An operating microscope with higher magnification and higher resolution for cerebral aneurysm surgery: preliminary experience-technical note.

We describe a higher magnifying power operating microscope system to improve one method of high-quality microsurgical clipping for cerebral aneurysm in some cases. This higher magnification is achieved by a new lens design in the optical system, which makes the image of the object very clear at high magnifications (distinctiveness of 7 µm). This higher-resolution operating microscope system provides the surgeon with higher-magnified images (at the maximum of more than 30× magnifications as each working distance) in the operating field. The magnifications can be changed from low power (2.9×) to high power (62.0×) depending on the circumstances in a given procedure. We have used this operating microscope system on 11 patients with microsurgical clipping for cerebral aneurysms. Microsurgical treatment could be performed safely and precisely. All aneurysms were treated without any technical complications. We think that the use of this microscope would have potential benefits for microsurgical treatment for cerebral aneurysms because of better visualization.

Effect of carotid endarterectomy on cognitive function in patients with asymptomatic carotid artery stenosis.

BACKGROUND: This study was conducted to determine if patients with asymptomatic carotid artery stenosis show cognitive function decline, and if they experience any changes in cognitive function after carotid endarterectomy (CEA). METHOD: Cognitive function was examined in 15 patients (12 males and three females, 70.0 ± 6.5 years) with asymptomatic carotid artery stenosis before and 3 months after CEA. Cognitive function was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), two subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R 2 subtests), and the Japanese version of National Adult Reading Test (JART). The patients' average scores were compared with the normal average by one-sample t-tests, and the before and after scores were compared with paired t-tests. Changes in each patient were calculated from difference before and after CEA using 95 % confidence intervals. RESULTS: Before surgery, patients showed significant cognitive decline in RBANS total scale and immediate memory, language, and attention. At 3 months after CEA, the total scale and the immediate memory were not significantly different from the normal average. The average total scale score, the immediate memory and attention, and the WAIS-R 2 subtests scores were increased after treatment. Changes in each patient were calculated from the scores before and after CEA. At 3 months after CEA, the rate of increase in RBANS scores were 60.0 % of the patients for immediate memory, 26.7 % for visuospatial/constructional, 33.3 % for language and attention, 26.7 % for delayed memory, 47.7 % for total scale and 26.7 % for WAIS-R 2 subtests. Thus, so-called asymptomatic patients exhibit mild cognitive impairment before surgery, but after CEA, patients recover normal memory abilities. CONCLUSIONS: Our findings of mild cognitive dysfunction in asymptomatic patients suggest that they might be symptomatic after all.

A proposal for standardized analysis of the results of microvascular decompression for trigeminal neuralgia and hemifacial spasm.

BACKGROUND: The purpose of this study was to evaluate and analyze overall postoperative results from microvascular decompression (MVD) by combining the cure rate of symptoms with the complication rate. A new scoring system for obtaining objective surgical results from MVD for trigeminal neuralgia (TN) and hemifacial spasm (HFS) is proposed to document treatment results using consistent criteria in a standardized manner. METHOD: Surgical results combining complications , if any, were obtained from a questionnaire sent to patients who had undergone surgery for TN or HFS in recent years and had been followed-up for more than 1 year after surgery (TN patients, n = 54; HFS patients, n = 81) When surgical outcome is complete resolution of symptoms, the efficacy of surgery (E) is designated E-0, but when moderate symptoms are still persist postoperatively, the score is designated E-2. When no complications are seen after surgery, the complication score (C) is C-0, while the score is C-2 if troublesome complications remain. In addition, total evaluation of the results (T) is judged by combining the E and C scores. For example, when E is 0, and C is C-2, the total evaluation is scored as T-2, which is diagnosed as fair. FINDINGS: The response rate of the questionnaire was 80.7% (109/135). Overall surgical data were evaluated and analyzed using our new scoring system. Analysis of the collected data revealed an outcome of T-0 was 70% (35/50 patients) and T-1 was 24% (12/50) and T-2 was 6% (3/50) in TN, whereas in HFS, T-0 was 61% (36/59) and T-1 was 27.1% (16/59) and T-2 was 6.8% (4/59) and T-3 was 5.1% (3/59). CONCLUSION: The total results of MVD should be evaluated and analyzed by combining the cure rate of symptoms together with the complication rate. This new scoring system could allow much more objective analysis of the results of following MVD. Adopting this scoring system to objectively judge treatment results for TN and HFS, individual surgeons can compare their own overall surgical results with those of other institutes. Comparative results of MVD can also be provided to patients considering therapy to allow informed decision-making on the basis of good quality evidence.

New dried human amniotic membrane is useful as a substitute for dural repair after skull base surgery.

Objectives Cerebrospinal fluid (CSF) leakage is an undesirable complication of skull base surgery. We used dried human amniotic membrane (AM) as a patch graft for dural repair to determine its efficacy in preventing CSF leakage. Design Frontoparietal craniotomy and removal of dura were performed in 20 Wistar rats. A dried AM was placed to cover the dural defect without suturing in 16 animals. In four animals, an expanded polytetrafluoroethylene was implanted. At 2 weeks and 1, 3, and 6 months, histological examination was performed. Dried AM was also used as a substitute in 10 patients who underwent skull base surgery, after approval by the Ethics Committee of the University of Toyama. Results At 2 weeks after implantation, thick connective tissue completely enclosed the dried AM. At 1 month after implantation, the connective tissue became thin and the implanted AM shortened. At 3 and 6 months after implantation, histological examination revealed disappearance of the dried AM and formation of membranous tissue. In the clinical study, neither CSF leakage nor clinical adverse reactions directly related to the dried AM were observed. Conclusion Dried human AM appears to be an ideal substitute for dura, since it is replaced by natural tissue.

Clear cell meningioma with histologically aggressive appearance and clinically aggressive behavior: a case report.

Clear cell meningioma (CCM) is an uncommon variant of meningioma, corresponding to WHO grade II. We present a case of CCM with histologically aggressive appearance and clinically aggressive behavior. The tumor demonstrated rapid regrowth and brain metastasis. The histological progression from the ordinal CCM to the atypical area and higher MIB-1 index was observed. We assume that the short time of recurrence and metastasis may result from atypical histological features in our case. If the CCM has a histologically aggressive appearance as in our case, we suggest that postoperative adjuvant radiotherapy should be performed despite total resection of the tumor.

Nationwide investigation of the current status of therapeutic neuroendoscopy for ventricular and paraventricular tumors in Japan.

OBJECT: The authors report their investigation on the current status of neuroendoscopic biopsy for ventricular and paraventricular tumors as well as treatment for associated hydrocephalus in Japan. METHODS: Patients who had undergone therapeutic neuroendoscopy between 2005 and 2009 were included in this study. The main items examined were age; sex; localization of tumor; pathological diagnosis using biopsy; the presence, treatment, and efficacy of treatment of associated hydrocephalus; perioperative complications; activities of daily living (ADL) before and after therapeutic neuroendoscopy; and the presence of dissemination during the postoperative course. RESULTS: Seven hundred fourteen patients from 123 sites (462 male and 252 female patients, mean age 33.3 years) were enrolled. Localization of the tumor was mainly classified into the lateral ventricle in 91 patients, the third ventricle in 339, the fourth ventricle in 18, the suprasellar region in 75, and other paraventricular areas in 191 patients. The most commonly observed tumors were germ cell tumors in the third ventricle (177 cases [39%]), cystic lesions in the suprasellar region (56 cases [75%]), and astrocytic tumors in the thalamus-basal ganglia (71 cases [38%]). Although 641 (92.8%) of 691 patients could receive neuroendoscopic diagnosis using biopsy, the diagnosis obtained with endoscopic biopsy differed from the final diagnosis based on subsequent craniotomy in 18 patients and clinical course in 3 patients. Of these 21 patients, 7 had astrocytic tumors, 4 had pineal tumors, 6 had germ cell tumors, and 4 had other tumors. The final diagnostic accuracy rate was 89.7%. Associated hydrocephalus was observed in 517 patients (72.4%), of whom 316 and 39 underwent third ventriculostomy and fenestration of the septum, respectively. The response rates were 96.2% and 89.7%, respectively. Third ventriculostomy was required for recurrence of hydrocephalus in 41 patients (13.0%), and the long-term response rate was therefore 83.2% (263 of 316 patients). Perioperative complications other than fever, such as new onset of or progressive hydrocephalus, infection due to CSF leakage, and bleeding in the ventricle or tumor, were found in 81 patients (11.3%). The median Karnofsky Performance Scale score before endoscopic surgery was 80, but it increased to 90 after surgery. The score was thus significantly increased after surgery (p < 0.0001, Mann-Whitney U-test). Activities of daily living after surgery decreased due to perioperative complications in 15 patients (2.1%). The incidence of new dissemination after endoscopic biopsy was 6.8% and not high compared with routine surgical treatment. CONCLUSIONS: The authors concluded that neuroendoscopic diagnosis using biopsy for ventricular and paraventricular tumors is adequately accurate and safe. It was demonstrated that endoscopic procedures play important roles not only in the treatment of hydrocephalus associated with intra- and paraventricular tumors but also in significantly improving ADL. Furthermore, the long-term outcome of endoscopic third ventriculostomy was clearly favorable.

Basic training model for supermicrosurgery: a novel practice card model.

Supermicrosurgery has been developed and reported the anastomosis of vessels with diameters of about 0.5 mm or less. The anastomosis of vessels of about 0.5 mm or less in diameter is technically more difficult than 1.0 mm or larger. This article describes a novel practice card model for acquiring basic supermicrosurgical techniques. A practice card is composed of very small-caliber silicone tubes simulating very small-caliber vessels and a thick paper. The silicone tube external diameters are 0.3, 0.5, or 0.7 mm. The thickness of the tube wall is 0.05 mm. Microsurgeons can easily begin to practice and warm up the supermicrosurgical suturing and anastomosing techniques using this nonvital practice card under a personal desk stereomicroscope in the office and an operating microscope in the operating room. This training model is a simple system for practicing basic supermicrosurgical techniques repeatedly and for warming up before a supermicrosurgical operation. This article also describes basic training regarding its use at high magnifications. This training-based supermicrosurgical skill may become a valuable technique for microsurgeons in many specialties.

Bilateral subthalamic deep brain stimulation for camptocormia associated with Parkinson's disease.

BACKGROUND: Few multiple case studies of the effects of deep brain stimulation for camptocormia associated with Parkinson's disease have been reported. Although deep brain stimulation was in some cases not effective against camptocormia, it is unclear in which types of patients it was effective in treating camptocormia. OBJECTIVE: We treated 4 Parkinson's disease patients with camptocormia and evaluated their paraspinal muscle status by computed tomography to specify the characteristics of cases of effective treatment. METHODS: The 2 female and 2 male patients in this study were 60-69 years old, with a disease duration from onset to surgery of 7-13 years and a follow-up period of 18-40 months. The electrodes were implanted bilaterally in the subthalamic nuclei. RESULTS: Camptocormia was improved in 3 cases, and was unchanged in the remaining case although other parkinsonian symptoms improved. The computed tomography number of paraspinal muscle in the unimproved patient was much smaller than that in the improved patients. CONCLUSIONS: A relationship may exist between improvement of camptocormia and severity of paraspinal muscle degeneration.

Unilateral anterior interhemispheric approach for anterior communicating artery aneurysms with horizontal head position--technical note.

The horizontal head position was adopted in the unilateral anterior interhemispheric approach to treat an anterior communicating artery (ACoA) aneurysm. The patient was placed in the supine position. The patient's head was rotated to the right to orient the midline horizontally, and tilted 45 degrees superiorly. After bicoronal skin incision and bifrontal craniotomy, the dura on the right side (downside) was opened. Dissection of the right interhemispheric fissure allowed gravity to retract the right (downside) hemisphere, which fell away from the falx, while the falx supported the upside hemisphere. The present approach was used in three patients with ACoA aneurysm between January 2009 and April 2010. The aneurysms were adequately clipped with this approach. No complication related to the approach occurred. No patients exhibited anosmia after surgery. This approach is useful for ACoA aneurysms.

Thoracic vertebral cavernous hemangioma in a schizophrenic patient--case report.

A 55-year-old man presented with gait disturbance, incontinence, and back pain. He had a medical history of schizophrenia for the past 35 years. Computed tomography (CT) and magnetic resonance imaging suggested thoracic vertebral hemangioma. Dynamic CT incidentally detected a hepatic hemangioma. Laminectomy of T3 and T4, resection of the epidural hemangioma, and rigid instrumentation between T1 and T6 using rod and hook systems were performed. Postoperatively, his symptoms completely disappeared and the histological diagnosis was capillary hemangioma. Schizophrenic patients have diminished sensitivity to pain or other symptoms, so neurological symptoms may become severe. However, early and appropriate treatment can result in satisfactory neurological outcome. The patient had a rare association of vertebral hemangioma and hepatic hemangioma, which may be a chance occurrence.

Middle cranial fossa arachnoid cyst presenting with subdural effusion and endoscopic detection of tear of the cyst--case report.

A 15-year-old boy presented with a case of middle cranial fossa arachnoid cyst associated with subdural effusion and manifesting as headache and vomiting after minor head injury. Computed tomography disclosed a cystic lesion in the left middle cranial fossa and ipsilateral subdural effusion. Fundoscopic examination revealed papilledema. A small tear of the cyst wall was confirmed endoscopically. Fenestration of the cyst was performed under the operating microscope. Postoperative course was uneventful. The tear in the outer wall of an arachnoid cyst may suggest the mechanism of occurrence of subdural effusion associated with middle cranial fossa arachnoid cyst.

Cavernous sinus cavernous hemangioma largely extending into the sella turcica and mimicking pituitary adenoma: case report.

A 77-year-old female presented with a rare cavernous sinus cavernous hemangioma with extension to the sella turcica, neuroradiologically mimicking nonfunctioning pituitary macroadenoma. The lesion was partially removed via transsphenoidal surgery, and the histological diagnosis was cavernous hemangioma. After stereotactic radiosurgery using a cyber knife, the lesion decreased in size. Stereotactic radiosurgery may be a good option for cavernous sinus cavernous hemangioma with high risk of surgical bleeding.

Consequences of preoperative evaluation of patterns of drainage of the cavernous sinus in patients treated using the anterior transpetrosal approach.

Extradural procedures in an anterior transpetrosal approach (ATPA) may interrupt the route of drainage from the superficial middle cerebral veins (SMCVs) and the cavernous sinus (CS) to the pterygoid venous plexus at the temporal skull base. Patterns of drainage of the SMCV and the CS and the results of surgery were examined in 12 patients with petroclival lesions treated using the ATPA between 2000 and 2008. The angiographic patterns of drainage of the SMCV were examined in 22 sides of the 12 patients. The SMCV drained into the sphenoparietal sinus in 12 sides, the sphenobasal veins in 4 sides, and the cortical veins in 6 sides. The patterns of drainage of the CS were examined on 12 sides in which the SMCV drained into the sphenoparietal sinus. The CS drained into the inferior petrosal sinus (IPS) in 7 sides and equally into the pterygoid plexus and IPS in 3 sides. The CS drained mainly into the pterygoid plexus in 2 sides of 2 patients, who both suffered temporal lobe swelling postoperatively. The pattern of venous drainage of the CS must be considered in planning surgical approaches to petroclival lesions. In patients with a well-developed pterygoid plexus, surgical interruption of this drainage route may be a cause of injury of the temporal lobe.

Synchronous multifocal osteosarcoma involving the skull presenting with intracranial hemorrhage -case report-.

A 40-year-old man presented with a rare case of synchronous multifocal osteosarcoma involving the skull associated with intracerebral hemorrhage, manifesting as sudden headache and left homonymous hemianopia. Computed tomography revealed a skull tumor in the right occipital bone and intracerebral hemorrhage in the right occipital lobe. Gross total resection of the skull tumor with hematoma was performed. The histological diagnosis was osteosarcoma. The tumor cells had invaded into the surrounding brain parenchyma, resulting in intracerebral hemorrhage.

[Cerebral infarction suspected due to dissection of intracranial carotid artery in 2 children].

Intracranial cerebral artery dissection in children is very rare. We report 2 children who were diagnosed as having cerebral infarction which was suspected to be due to dissection of intracranial cerebral artery. Case 1: An 11-year-old girl presented with conscious disturbance and hemiparesis after seizure. Computed tomography (CT) showed cerebral infarction in the right frontal lobe. Her symptoms did not change, but angiography demonstrated reversible change. She received conservative therapy. Case 2: A 10-year-old boy complained of headache, and presented nausea and monoparesis of the left upper extremity. CT showed cerebral infarction in the right frontal lobe. He received superficial temporal artery-middle cerebral artery anastomosis because his symptoms fluctuated. In both cases, cerebral angiography showed string sign from the supraclinoid portion of the internal carotid artery to the middle and the anterior cerebral artery. Follow-up angiography showed improvement of stenosis. In pediatric cases of cerebral artery dissection, improvement with conservative therapy is frequently reported. It is necessary to follow-up such patients closely using magnetic resonance angiography or conventional angiography to determine whether or not surgery is indicated.

Anomia for people's names after left anterior temporal lobe resection--case report.

A 47-year-old man was admitted to our hospital with an intrinsic brain tumor in the left anterior temporal lobe. Preoperative sodium thiopental test demonstrated left hemispheric dominance. Awake craniotomy was performed for dominant-hemispheric tumor resection using language mapping to identify the stimulation-induced positive language area. The tasks of object naming and repetition were used, along with specific tests for famous people's names. The language area was detected on the superior temporal gyrus and preserved. Following surgery, this patient was unable to retrieve the names of famous individuals (i.e. anomia for people's name) despite preservation of semantic knowledge for those individuals. This anomia for people's names showed no improvement at all for a period of 15 months. This case report and other sporadic cases with this type of deficit reveal the left anterior temporal lobe is an important brain area for retrieving people's names.

A rare astrocytic tumor with rhabdoid features.

We report an extremely rare tumor presenting with rhabdoid features in the left temporoparietal lobe near the trigone in an 18-year-old Japanese man. This tumor mainly consisted of medium to large round cells that proliferated diffusely and incoherently with a scant extracellular matrix. These tumor cells had an eccentric nucleus and an eosinophilic cytoplasm containing inclusion bodies and bundles of intermediate filaments. The nuclei of these cells were vesicular with prominent nucleoli. This tumor had an area appearing to be diffuse astrocytoma peripherally and lacked a primitive neuroectodermal tumor component, a mesenchymal component, and epithelial differentiation. INI expression, which is not observed in atypical teratoid/ rhabdoid tumor (AT/RT), was found in this tumor. From these findings, we concluded that this tumor was not AT/RT but an astrocytic tumor with rhabdoid features. We also concluded that the tumor cells exhibiting rhabdoid features had secondarily arisen from the peripheral area presenting an appearance of diffuse astrocytoma.