Sunil Manjila

Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma: clinical article.

OBJECT Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose-escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM). METHODS Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation. RESULTS Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals-Case Medical Center). Their average age was 55 years (range 34-69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70-90). The mean tumor volume was 6.8 ± 5 cm(3) (range 2.6-19 cm(3)), the percentage of tumor treated was 78% ± 12% (range 57%-90%), and the conformality index was 1.21 ± 0.33 (range 1.00-2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62-767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose. CONCLUSIONS NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. CLINICAL TRIAL REGISTRATION NO.: NCT00747253 ( ClinicalTrials.gov ).

Embryonal tumors with abundant neuropil and true rosettes: 2 illustrative cases and a review of the literature

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a recently identified variant of primitive neuroectodermal tumor, with fewer than 50 cases reported in the literature to date. Histologically, this tumor has features of ependymoblastoma and neuroblastoma, demonstrating areas of fine fibrillary neuropil intermingled with ependymoblastic rosettes and zones of undifferentiated neuroepithelial cells. However, ETANTR is distinguished pathologically from other embryonal tumors by the striking abundance of neuropil. Clinically, ETANTRs have shown high malignant potential and poor clinical outcome despite aggressive treatment. The authors describe 2 illustrative surgical cases of ETANTR, one involving the longest reported survival in the literature to date. The other had a poor outcome despite high-dose adjuvant chemotherapy with sequential autologous hematopoietic stem cell rescue. The authors review the natural history and treatment strategies available for this unusual malignant pediatric brain tumor.

Cerebral amyloid angiopathy–associated intracerebral hemorrhage: pathology and management

Amyloid angiopathy-associated intracerebral hemorrhage (ICH) comprises 12%-15% of lobar ICH in the elderly. This growing population has an increasing incidence of thrombolysis-related hemorrhages, causing the management of hemorrhages associated with cerebral amyloid angiopathy (CAA) to take center stage. A concise reference assimilating the pathology and management of this clinical entity does not exist. Amyloid angiopathy-associated hemorrhages are most often solitary, but the natural history often progresses to include multifocal and recurrent hemorrhages. Compared with other causes of ICH, patients with CAA-associated hemorrhages have a lower mortality rate but an increased risk of recurrence. Unlike hypertensive arteriolar hemorrhages that occur in penetrating subcortical vessels, CAA-associated hemorrhages are superficial in location due to preferential involvement of vessels in the cerebral cortex and meninges. This feature makes CAA-associated hemorrhages easier to access surgically. In this paper, the authors discuss 3 postulates regarding the pathogenesis of amyloid hemorrhages, as well as the established clinicopathological classification of amyloid angiopathy and CAA-associated ICH. Common inheritance patterns of familial CAA with hemorrhagic strokes are discussed along with the role of genetic screening in relatives of patients with CAA. The radiological characteristics of CAA are described with specific attention to CAA-associated microhemorrhages. The detection of these microhemorrhages may have important clinical implications on the administration of anticoagulation and antiplatelet therapy in patients with probable CAA. Poor patient outcome in CAA-associated ICH is associated with dementia, increasing age, hematoma volume and location, initial Glasgow Coma Scale score, and intraventricular extension. The surgical management strategies for amyloid hemorrhages are discussed with a review of published surgical case series and their outcomes with a special attention to postoperative hemorrhage.

The role of cancer stem cells in glioblastoma

Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade. Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells that contributes to tumor propagation, maintenance, and treatment resistance. Cancer stem cells are functionally defined by their ability to self-renew and to differentiate, and they constitute the diverse hierarchy of cells composing a tumor. When xenografted into an appropriate host, they are capable of tumorigenesis. Given the critical role of cancer stem cells in the pathogenesis of glioblastoma, research into their molecular and phenotypic characteristics is a therapeutic priority. In this review, the authors discuss the evolution of the cancer stem cell model of tumorigenesis and describe the specific role of cancer stem cells in the pathogenesis of glioblastoma and their molecular and microenvironmental characteristics. They also discuss recent clinical investigations into targeted therapies against cancer stem cells in the treatment of glioblastoma.

Pharmacological management of acromegaly: a current perspective

Acromegaly is a chronic disorder of enhanced growth hormone (GH) secretion and elevated insulin-like growth factor–I (IGF-I) levels, the most frequent cause of which is a pituitary adenoma. Persistently elevated GH and IGF-I levels lead to substantial morbidity and mortality. Treatment goals include complete removal of the tumor causing the disease, symptomatic relief, reduction of multisystem complications, and control of local mass effect. While transsphenoidal tumor resection is considered first-line treatment of patients in whom a surgical cure can be expected, pharmacological therapy is playing an increased role in the armamentarium against acromegaly in patients unsuitable for or refusing surgery, after failure of surgical treatment (inadequate resection, cavernous sinus invasion, or transcapsular intraarachnoid invasion), or in select cases as primary treatment. Three broad drug classes are available for the treatment of acromegaly: somatostatin analogs, dopamine agonists, and GH receptor antagonists. Somatostatin analogs are considered as the first-line pharmacological treatment of acromegaly, although efficacy varies among the different formulations. Octreotide long-acting release (LAR) appears to be more efficacious than lanreotide sustained release (SR). Lanreotide Autogel (ATG) has been shown to result in similar biological control as octreotide LAR, and there may be a benefit in switching from one to the other in some cases of treatment failure. The novel multireceptor somatostatin analog pasireotide, currently in Phase II clinical trials, also shows promise in the treatment of acromegaly. Dopamine agonists have been the earliest and most widely used agents in the treatment of acromegaly but have been found to be less effective than somatostatin analogs. In this class of drugs, cabergoline has shown greater efficacy and tolerability than bromocriptine. Dopamine agonists have the advantage of oral administration, resulting in increased use in select patient groups. Selective GH receptor antagonists, such as pegvisomant, act by blocking the effects of GH, resulting in decreased IGF-I production despite persistent elevation of GH serum levels. Thus far, tumor growth has not been a concern during pegvisomant therapy. However, combination treatment with somatostatin analogs may counteract these effects. The authors discuss the latest guidelines for biochemical cure and highlight the efficacy of combination therapy. In addition, the effects of pharmacological presurgical treatment on surgical outcome are explored.

Stereotactic radiosurgery with and without embolization for intracranial arteriovenous malformations: a systematic review and meta-analysis.

OBJECT The effectiveness and risk of stereotactic radiosurgery (SRS) in the management of partially embolized intracranial arteriovenous malformations (AVMs) remain controversial. The aim of this analysis was to assess current evidence regarding the efficiency and safety of SRS for AVM patients with and without prior embolization. METHODS To compare SRS in patients with and without embolization, the authors conducted a meta-analysis of studies by searching the literature via PubMed and EMBASE for the period between January 2000 and December 2013, complemented by a hand search. Primary outcome was the rate of AVM obliteration on a 3-year follow-up angiogram. Secondary outcome was the rate of hemorrhage at 3 years after SRS. Tertiary outcome was permanent neurological deficits related to radiation-induced changes. RESULTS Ten studies eligible for analysis included 1988 patients: 593 had undergone embolization followed by SRS and 1395 had undergone SRS alone. The AVM obliteration rate was significantly lower in patients who had undergone embolization followed by SRS than in those who had undergone SRS alone (41.0% vs 59%, OR 0.46, 95% CI 0.37-0.56, p < 0.00001). However, the rates of hemorrhage (7.3% vs 5.6%, OR 1.17, 95% CI 0.74-1.83, p = 0.50) and permanent neurological deficits related to radiation-induced changes (3.3% vs 3.4%, OR 1.41, 95% CI 0.64-3.11, p = 0.39) were not significantly different between the two groups. CONCLUSIONS Embolization before SRS significantly decreases the AVM obliteration rate. However, there is no significant difference in the risk of hemorrhage and permanent neurological deficits after SRS alone and following embolization. Further validation by well-designed prospective or randomized cohort studies is still needed.

Virtual reality simulation: basic concepts and use in endoscopic neurosurgery training.

IntroductionVirtual reality simulation is a promising alternative to training surgical residents outside the operating room. It is also a useful aide to anatomic study, residency training, surgical rehearsal, credentialing, and recertification.DiscussionSurgical simulation is based on a virtual reality with varying degrees of immersion and realism. Simulators provide a no-risk environment for harmless and repeatable practice. Virtual reality has three main components of simulation: graphics/volume rendering, model behavior/tissue deformation, and haptic feedback. The challenge of accurately simulating the forces and tactile sensations experienced in neurosurgery limits the sophistication of a virtual simulator. The limited haptic feedback available in minimally invasive neurosurgery makes it a favorable subject for simulation.ConclusionsVirtual simulators with realistic graphics and force feedback have been developed for ventriculostomy, intraventricular surgery, and transsphenoidal pituitary surgery, thus allowing preoperative study of the individual anatomy and increasing the safety of the procedure. The authors also present experiences with their own virtual simulation of endoscopic third ventriculostomy.

Management of anterior inferior cerebellar artery aneurysms: an illustrative case and review of literature

Aneurysms of the anterior inferior cerebellar artery (AICA) are relatively rare among intracranial aneurysms. They can occur in 1 of 3 regions of the AICA: 1) craniocaudal (high or low riding), 2) mediolateral-premeatal (proximal), and 3) meatal-postmeatal (distal). The management strategies for treatment differ according to the location and configuration of the aneurysm. The existing body of neurosurgical literature contains articles published on aneurysms arising from the AICA near the basilar artery (BA), intracanalicular/meatal aneurysms, and distal AICA. Several therapeutic options exist, encompassing microsurgical and endovascular techniques. The authors describe a case of treatment involving a large BA-AICA aneurysm approached via exposure of the presigmoid dura using a retromastoid suboccipital craniectomy and partial petrosectomy. Treatment of these lesions requires detailed knowledge of the anatomy, and an anatomical overview of the AICA with its arterial loops and significant branches is presented, including a discussion of the internal auditory (labyrinthine) artery, recurrent perforating arteries, subarcuate artery, and cerebellosubarcuate artery. The authors discuss the various surgical approaches (retromastoid, far lateral, subtemporal, and transclival) with appropriate illustrations, citing the advantages and disadvantages in accessing these AICA lesions in relation to these approaches. The complications of these different surgical techniques and possible clinical effects of parent artery occlusion during AICA surgery are highlighted.

History of the Kleeblattschädel deformity: Origin of concepts and evolution of management in the past 50 years

The history and evolution of surgical strategies for the treatment of Kleeblattschädel deformity are not well described in the medical literature. Kleeblattschädel anomaly is one of the most formidable of the craniosynostoses, requiring a multidisciplinary team for surgical treatment. The initial descriptions of this cloverleaf deformity and the evolution of surgical treatment are detailed in the present report. Two illustrative cases of Kleeblattschädel deformity, syndromic and nonsyndromic craniosynostoses treated by the senior authors, are also described along with insights into operative strategies.

Non‐Langerhans cell histiocytosis with isolated CNS involvement: An unusual variant of Erdheim‐Chester disease

Benign histiocytic proliferations are identified by their component cells and classified as either Langerhans cell histiocytosis or non‐Langerhans cell histiocytosis. We report a 58‐year‐old Caucasian woman who presented with diabetes insipidus and was found to harbor a large suprasellar mass. Histopathological analysis was consistent with non‐LCH. The differential diagnoses included juvenile xanthogranuloma, adult‐onset xanthogranuloma, xanthoma disseminatum, Rosai‐Dorfman disease, and Erdheim‐Chester disease. Immunohistochemical examination demonstrated a proliferation of large lipid‐laden histiocytic cells which were positive for CD68, negative for S100 protein, and showed only faint, background staining for CD1a. We present a case of an autopsy‐confirmed non‐Langerhans cell histiocytosis limited to the central nervous system and evaluated with both immunohistochemical and ultrastructural studies. Based on the multifocality, anatomic distribution, and immunostaining features, a diagnosis of Erdheim‐Chester disease was made. This is only the second reported case of Erdheim‐Chester disease with intracranial involvement but absence of extracerebral manifestations. Given the overlapping clinicopathologic, radiographic, and immunohistochemical profiles, differentiating between these rare histiocytic disorders can often present a significant diagnostic challenge. A systematic approach using all available clinical, laboratory, radiographic, histologic, immunohistochemical and ultrastructural data is essential for proper discrimination between the numerous histiocytoses.