CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma.

The alkylating agent, temozolomide (TMZ), is the most commonly used chemotherapeutic for the treatment of glioblastoma (GBM). The anti-glioma effect of TMZ involves a complex response that includes G2-M cell cycle arrest and cyclin-dependent kinase 1 (CDK1) activation. While CDK1 phosphorylation is a well-described consequence of TMZ treatment, we find that TMZ also robustly induces CDK1 expression. Analysis of this pathway demonstrates that CDK1 is regulated by NF-κB via a putative κB-site in its proximal promoter. CDK1 was induced in a manner dependent on mature p50 and the atypical inhibitor κB protein, BCL-3. Treatment with TMZ induced binding of NF-κB to the κB-site as assessed by gel shift analysis and chromatin immunoprecipitation. Examination of a CDK1 promoter-reporter demonstrated the functional relevance of the κB-site and underlined the requirement of p50 and BCL-3 for activation. Targeted knockdown of CDK1 or chemical inhibition with the selective CDK1 inhibitor, RO-3306, potentiated the cytotoxic effect of TMZ. These results identify CDK1 as an NF-κB target gene regulated by p50 and BCL-3 and suggest that targeting CDK1 may be a strategy to improve the efficacy of TMZ against GBM.

Temozolomide Treatment Induces lncRNA MALAT1 in an NF-κB and p53 Codependent Manner in Glioblastoma.

Alkylating chemotherapy is a central component of the management of glioblastoma (GBM). Among the factors that regulate the response to alkylation damage, NF-κB acts to both promote and block cytotoxicity. In this study, we used genome-wide expression analysis in U87 GBM to identify NF-κB-dependent factors altered in response to temozolomide and found the long noncoding RNA (lncRNA) MALAT1 as one of the most significantly upregulated. In addition, we demonstrated that MALAT1 expression was coregulated by p50 (p105) and p53 via novel κB- and p53-binding sites in the proximal MALAT1 coding region. Temozolomide treatment inhibited p50 recruitment to its cognate element as a function of Ser329 phosphorylation while concomitantly increasing p53 recruitment. Moreover, luciferase reporter studies demonstrated that both κB and p53 cis-elements were required for efficient transactivation in response to temozolomide. Depletion of MALAT1 sensitized patient-derived GBM cells to temozolomide cytotoxicity, and in vivo delivery of nanoparticle-encapsulated anti-MALAT1 siRNA increased the efficacy of temozolomide in mice bearing intracranial GBM xenografts. Despite these observations, in situ hybridization of GBM specimens and analysis of publicly available datasets revealed that MALAT1 expression within GBM tissue was not prognostic of overall survival. Together, these findings support MALAT1 as a target for chemosensitization of GBM and identify p50 and p52 as primary regulators of this ncRNA. SIGNIFICANCE: These findings identify NF-κB and p53 as regulators of the lncRNA MALAT1 and suggest MALAT1 as a potential target for the chemosensitization of GBM.

Convection-Enhanced Delivery of Polymeric Nanoparticles Encapsulating Chemotherapy in Canines with Spontaneous Supratentorial Tumors.

BACKGROUND: Despite aggressive multimodal treatment, survival for patients with glioblastoma remains dismal. One obstacle to improving patient outcomes is the difficulty in delivering adequate therapeutic to the central nervous system due to the presence of the blood-brain barrier. Although direct drug infusion by convection-enhanced delivery (CED) can bypass the blood-brain barrier and facilitate delivery to intracranial tumors, determining the distribution of delivered therapeutic remains problematic. Image guidance is a strategy that can optimize the accuracy of therapeutic delivery. METHODS: Here we performed an open-label clinical trial in 10 pet dogs with spontaneous intracranial tumors to examine the target coverage accuracy of delivering polymeric magnetite nanoparticles (PMNPs) encapsulating temozolomide (TMZ). A modified small animal frame was applied to the head of each subject, and PMNPs were delivered stereotactically to the center of the tumor. Magnetic resonance imaging (MRI) was performed immediately postoperatively to examine PMNP distribution, and the animals were followed until death. RESULTS: Nine of the 10 dogs underwent PMNP infusion without complications. No infusate backflow was observed during any procedure. In 70% of the cases, the infusion accurately targeted the tumor mass, as determined by the presence of PMNP signal in the tumor on immediate postoperative MRI. CONCLUSIONS: These data suggest that CED of PMNPs carrying TMZ is safe in dogs with intracranial tumors and can lead to nanoparticle distribution in the region of the target. Image guidance is an important adjunct to CED, because distribution is unpredictable, with the potential for missed target delivery.

Long-term follow-up analysis of microsurgical clip ligation and endovascular coil embolization for dorsal wall blister aneurysms of the internal carotid artery.

Blister aneurysms at non-branching sites of the dorsal internal carotid artery (dICA) are fragile, rare, and often difficult to treat. The purpose of this study is to address the demographics, treatment modalities, and long-term outcome of patients treated for dICA blister aneurysms. A retrospective review of medical records identified all consecutive patients who presented with a blister aneurysm from 2002 to 2011 at our institution. Eighteen patients (M=7, F=11; mean age: 48.4±15.1years; range: 15-65years) harbored a total of 43 aneurysms, 25 of which were dorsal wall blister aneurysms of the ICA. Eleven (61.1%) patients presented with aneurysmal subarachnoid hemorrhage (aSAH), and 10 (55.6%) patients had multiple aneurysms at admission. Twelve patients had 18 aneurysms that were treated microsurgically. Five (41.7%) of these patients had a single recurrence that was retreated with subsequent repeat clip ligation. Six patients had 7 blister aneurysms that were treated with endovascularly. One (16.7%) of these patients had a single recurrence that was retreated with subsequent coil embolization. Postoperative vasospasm occurred in 8 (44.4%) patients, one of whom suffered from a stroke. This is one of the largest single-institution dICA blister aneurysm studies to date. There was no detected significant difference between microsurgical clip ligation and endovascular coil embolization in terms of surgical outcome. These blister aneurysms demonstrate a propensity to be associated with multiple cerebral aneurysms. Strict clinical and angiographic long-term follow-up may be warranted. STATEMENT OF SIGNIFICANCE: Blister aneurysms are focal wall defects covered by a thin layer of fibrous tissue and adventitia, lacking the usual collagenous layer. Due to their pathologically thin vessel wall, blister aneurysms are prone to rupture. The management of these rare and fragile aneurysms presents a number of challenges. Here, we address the long-term outcome of patients treated for blister aneurysms at non-branching sites of the dICA. The presented data and analysis is imperative to determine the necessary strict long-term clinical and angiographic follow-up.

Disseminated choroid plexus papillomas in adults: A case series and review of the literature.

Choroid plexus papillomas (CPPs) are uncommon, usually intraventricular, low-grade tumors, accounting for less than 1% of all intracranial neoplasms and 2-4% of brain tumors in children. Dissemination of CPPs to multiple levels of the neuraxis has been seldom observed. Thus far, only 26 adult patients have been reported in the English language literature. With some exceptions, disseminated CPPs have been observed in adults and involved multiple sites along the cerebrospinal fluid pathways. Occasionally, intraparenchymal extension has been documented, and secondary involvement of the suprasellar region has been reported in only five patients. Postoperative treatment of CPPs has not been standardized. Most recommended therapies have been extrapolated from a series of atypical papillomas or carcinomas of the choroid plexus in children. We herein report a series of three patients of disseminated choroid plexus papillomas providing additional insights into this relatively rare entity.

Long-Term Results of Various Operations for Lumbar Disc Herniation: Analysis of over 39,000 Patients.

OBJECTIVE: To determine the long-term follow-up of the various operations for lumbar disc herniation in a large patient population. SUBJECTS AND METHODS: Patients who had operations for lumbar disc herniation (microdiscectomy, endoscopic microdiscectomy and the 'classical operation', i.e. laminectomy/laminotomy with discectomy) were collected from the world literature. Patients who had follow-ups for at least 2 years were analyzed relative to the outcome. The outcome was graded by the patients themselves, and the operative groups were compared to one another. RESULTS: 39,048 patients collected from the world literature had had lumbar disc operations for disc herniations. The mean follow-up period was 6.1 years, and 30,809 (78.9%) patients reported good/excellent results. Microdiscectomy was performed on 3,400 (8.7%) patients. The mean follow-up was 4.1 years with 2,866 (84.3%) good/excellent results, while 1,101 (3.6%) patients had endoscopic microdiscectomy. There, the mean follow-up was 2.9 years with 845 (79.5%) good/excellent results. The classical operation was performed on 34,547 (88.5%) patients with a mean follow-up period of 6.3 years, and 27,050 (78.3%) patients had good/excellent results. These results mirror those with discectomy and the placement of prosthetic discs. CONCLUSIONS: The analysis of 39,048 patients with various operations for lumbar disc herniation revealed the same pattern of long-term results. Patients who had microdiscectomy, endoscopic microdiscectomy or the classical operation (laminectomy/laminotomy with discectomy) all had approximately 79% good/excellent results. None of the operative procedures gave a different outcome. l.

Decoy Receptor DcR1 Is Induced in a p50/Bcl3-Dependent Manner and Attenuates the Efficacy of Temozolomide.

Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53(+/+) glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.

Convection-enhanced delivery and in vivo imaging of polymeric nanoparticles for the treatment of malignant glioma.

A major obstacle to the management of malignant glioma is the inability to effectively deliver therapeutic agent to the tumor. In this study, we describe a polymeric nanoparticle vector that not only delivers viable therapeutic, but can also be tracked in vivo using MRI. Nanoparticles, produced by a non-emulsion technique, were fabricated to carry iron oxide within the shell and the chemotherapeutic agent, temozolomide (TMZ), as the payload. Nanoparticle properties were characterized and subsequently their endocytosis-mediated uptake by glioma cells was demonstrated. Convection-enhanced delivery (CED) can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. Infusion of nanoparticles does not result in observable animal toxicity relative to control. CED of TMZ-bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control. In conclusion, the described nanoparticle vector represents a unique multifunctional platform that can be used for image-guided treatment of malignant glioma. FROM THE CLINICAL EDITOR: GBM remains one of the most notoriously treatment-unresponsive cancer types. In this study, a multifunctional nanoparticle-based temozolomide delivery system was demonstrated to possess enhanced treatment efficacy in a rodent xenograft GBM model, with the added benefit of MRI-based tracking via the incorporation of iron oxide as a T2* contrast material in the nanoparticles.

Role of barbiturate coma in the management of focally induced, severe cerebral edema in children.

Barbiturates are widely used in the management of high intracranial pressure (ICP) caused by diffuse brain swelling. The cardiovascular, renal, and immunological side effects of these drugs limit them to last-line therapy. There are few published data regarding the role of barbiturates in focal brain lesions causing refractory elevated ICP and intraoperative brain swelling in the pediatric population. The authors here present 3 cases of nontraumatic, focally induced, refractory intracranial hypertension due to 2 tumors and 1 arteriovenous malformation, in which barbiturate therapy was used successfully to control elevated ICP. They focus on cardiovascular, renal, and immune function during the course of pentobarbital therapy. They also discuss the role of pentobarbital-induced hypothermia. From this short case series, they demonstrate that barbiturates in conjunction with standard medical therapy can be used to safely reduce postoperative refractory intracranial hypertension and intraoperative brain swelling in children with focal brain lesions.

Overcoming challenges associated with upright imaging of the cervicothoracic junction: a case report involving a novel repurposing of the O-arm.

BACKGROUND: Prior to the mobilization of patients with spinal fractures following treatment, it is important to confirm stability in the upright position. METHODS: A patient presented with T2 and T3 vertebral body fractures visible on recumbent CT. Supine and upright plain x-rays with additional swimmer's views were deemed suboptimal prior to mobilization. The default configuration of the O-arm was modified to enable imaging in the upright position. RESULTS: Images utilizing the O-arm were satisfactory and anatomic alignment confirmed in an upright position. It is believed that this is the first time the O-arm has been used for upright diagnostic imaging (off-label application). Excellent visualization of the cervicothoracic junction and upper thoracic regions was obtained in the desired upright position. CONCLUSION: The O-arm was used successfully to image spinal trauma in the upright position and may represent a new application of the device, potentially fulfilling a frequently unmet medical imaging need.

Facial herpes zoster infection precipitated by surgical manipulation of the trigeminal nerve during exploration of the posterior fossa: a case report.

INTRODUCTION: We present a case of herpes zoster infection (shingles) precipitated by surgical manipulation of the trigeminal nerve root during an attempted microvascular decompression procedure. The pathogenesis of this phenomenon, as well as the importance and role of prophylactic acyclovir in its management, are discussed. CASE PRESENTATION: A 54-year-old Caucasian man with a classical long-standing left-sided V2 and V3 division primary trigeminal neuralgia refractory to medical management, underwent posterior fossa exploration for microvascular decompression via a standard retromastoid craniectomy. The patient had immediate and complete relief from pain. Three days after the operation, he developed severely painful vesicles with V2 and V3 dermatomal distribution. Rather than the classical paroxysmal, lancinating type of trigeminal neuralgia, the pain experienced by the patient was of a constant burning nature. A clinical diagnosis of herpes zoster (shingles) was made after smear confirmation from microbiological testing. The patient was commenced on antiviral treatment with acyclovir. His vesicular rash and pain gradually subsided over the next two weeks. He remains asymptomatic one year later. CONCLUSIONS: Postoperative shingles precipitated by trigeminal nerve manipulation during surgery for trigeminal neuralgia can be a distressing and demoralizing experience for the patient. A careful preoperative history, early recognition, and prompt antiviral therapy is necessary.

Resolution of cranial nerve paresis after endovascular management of cerebral aneurysms.

BACKGROUND: This work aimed to study the outcome of endovascular (coiling and balloon occlusion) treatment in patients with aneurysmal mass effect (ophthalmoplegia due to third, fourth, or sixth CN paresis) and to compare it with the outcome of clipping (from the international literature). We looked at the outcome of endovascular treatment of CNP (third, fourth, and sixth) due to aneurysmal mass effect (PcomA aneurysms and intracavernous carotid aneurysms). METHODS: Between January 1999 and December 2004, 820 patients presented with aneurysmal SAH and/or mass effect. Eleven of these patients (1%) presented with third, and/or fourth, and/or sixth nerve dysfunctions and underwent endovascular treatment. The degree of the ophthalmoplegia was recorded at presentation, 2 months, 6 months, and yearly intervals thereafter. We correlated recovery of CNP to SAH, duration of the symptoms, degree of CNP, type of CNP, microvascular risks (age, diabetes mellitus, hypertension, and smoking), aneurysm size, and degree of coiling or balloon occlusion. RESULTS: The study showed a favorable outcome of endovascular treatment in the majority of patients. Resolution of CN dysfunctions occurred in 7 (64%) of 11 patients. The late follow-up showed that all the 7 patients are resuming normal life activities. This compares favorably to the results after clipping in [Leivo, Hemesniemi, Luukkonen, & Vapalahti, 1996] (41%). Presentation with SAH and isolated third CNP correlated with a better resolution of CNP (P < .05). CONCLUSION: Although mass effect remains after endovascular packing, CNP improves comparably to the recovery observed after surgical clipping. It seems likely that the decrease in aneurysmal pulsatility is responsible for the improvement of the CNP. The relatively atraumatic approach associated with endovascular management explains the favorable results. All previous reports assessed the outcome of only the third CNP after endovascular treatment in a very limited number of cases. To the best of our knowledge, this is the first study to assess the outcome of various CNP after endovascular treatment.

Compression of the rostral ventrolateral medulla by a vagal schwannoma of the cerebellomedullary cistern presenting with refractory neurogenic hypertension: case report.

OBJECTIVE: The rostral ventrolateral medulla is thought to serve as a final common pathway for the integration of central cardiovascular information and to be important for the mediation of central pressor responses. An association between essential hypertension and neurovascular compression of the rostral ventrolateral medulla has been reported. This may be mediated by an increase in sympathetic tone. CLINICAL PRESENTATION: Schwannomas arising from the lower cranial nerves (Cranial Nerves IX-XI) are rare, constituting only 3% of all intracranial schwannomas unassociated with neurofibromatosis. The majority of these tumors present as jugular foramen lesions and, less commonly, they occur along the extracranial course of these nerves. An intracisternal location is extremely rare. Fewer than 15 cases of pathologically proven intracisternal vagal schwannomas in the absence of neurofibromatosis have been reported. INTERVENTION: We report a case of vagal schwannoma in the cerebellomedullary cistern causing distortion of the vagal root entry zone and presenting with refractory neurogenic hypertension. Total microsurgical excision of this tumor, arising from one of the rootlets of the vagus nerve, was achieved. Immediately postoperatively, blood pressure decreased markedly, and despite our effort to maintain the blood pressure with fluids, the patient developed a cerebral infarction in the watershed zone. CONCLUSION: We discuss the proposed mechanism of hypertension, and the perioperative management, stressing blood pressure control. A review of the literature regarding vagal schwannomas is also presented. To the best of our knowledge, this is the first case report of a cerebellomedullary cistern vagal schwannoma presenting with neurogenic hypertension.