D. Ryan Ormond

The role of cytotoxic chemotherapy in the management of progressive glioblastoma

QuestionWhat is the impact of cytotoxic chemotherapy on disease control and survival in the adult patient with progressive glioblastoma?Target populationThis recommendation applies to adults patients with progressive glioblastoma.RecommendationsLevel IITemozolomide is recommended as superior to procarbazine in patients with first relapse of glioblastoma after having received nitrosourea chemotherapy or no prior cytotoxic chemotherapy at the time of initial therapy.The use of BCNU-impregnated biodegradable polymer wafers is recommended in the management of progressive glioblastoma as a surgical adjunct when cytoreductive surgery is indicated, taking into account the associated toxicities seen with this modality.Level IIIConsideration of a variety of cytotoxic chemotherapy agents of uncertain benefit is recommended in the setting of progressive glioblastoma based on the judgment of the treating physician taking into account the individual patients prior treatment exposure, systemic health, and likelihood of tolerance of the toxicities of any given agent. It is recommended in such cases that enrollment in available clinical trials be encouraged.

A second chance—reoperation in patients with failed surgery for intractable epilepsy: long-term outcome, neuropsychology and complications

Object Resective surgery is a safe and effective treatment of drug-resistant epilepsy. If surgery has failed reoperation after careful re-evaluation may be a reasonable option. This study was to summarise the risks and benefits of reoperation in patients with epilepsy. Methods This is a retrospective single centre study comprising clinical data, long-term seizure outcome, neuropsychological outcome and postoperative complications of patients, who had undergone a second resective epilepsy surgery from 1989 to 2009. Results A total of 66 patients with median follow-up of 10.3 years were included into the study. Fifty-one patients (77%) had surgery for temporal lobe epilepsy, the remaining 15 cases for extra-temporal lobe epilepsies. The most frequent histological findings were tumours (n=33, 50%), followed by dysplasia, gliosis (n=11, each) and hippocampus sclerosis (n=9). The main reasons for seizure recurrence were incomplete resection (59.1%) of the putative epileptogenic lesion. After reoperation 46 patients (69.7%) were completely seizure-free International League Against Epilepsy 1 (ILAE 1) at the last available follow-up. The neuropsychological evaluation demonstrated that repeated losses in the same cognitive domain, that is, successive changes from better to worse performance categories, were rare and that those losses after first surgery were followed by improvement rather than decline. However, reoperations lead to an increased rate of permanent neurological deficits (9%), overall surgical complications (9%) and visual field deficits (67%). Conclusions Reoperation after failed resective epilepsy surgery led to approximately 70% long-time seizure freedom and reasonable neuropsychological outcome. There is an increased risk of permanent postoperative neurological deficits, which should be taken into consideration when counselling for reoperation.

Stem Cell Therapy and Curcumin Synergistically Enhance Recovery from Spinal Cord Injury

Acute traumatic spinal cord injury (SCI) is marked by the enhanced production of local cytokines and pro-inflammatory substances that induce gliosis and prevent reinnervation. The transplantation of stem cells is a promising treatment strategy for SCI. In order to facilitate functional recovery, we employed stem cell therapy alone or in combination with curcumin, a naturally-occurring anti-inflammatory component of turmeric (Curcuma longa), which potently inhibits NF-κB. Spinal cord contusion following laminectomy (T9–10) was performed using a weight drop apparatus (10 g over a 12.5 or 25 mm distance, representing moderate or severe SCI, respectively) in Sprague-Dawley rats. Neural stem cells (NSC) were isolated from subventricular zone (SVZ) and transplanted at the site of injury with or without curcumin treatment. Functional recovery was assessed by BBB score and body weight gain measured up to 6 weeks following SCI. At the conclusion of the study, the mass of soleus muscle was correlated with BBB score and body weight. Stem cell therapy improved recovery from moderate SCI, however, it had a limited effect on recovery after severe SCI. Curcumin stimulated NSC proliferation in vitro, and in combination with stem cell therapy, induced profound recovery from severe SCI as evidenced by improved functional locomotor recovery, increased body weight, and soleus muscle mass. These findings demonstrate that curcumin in conjunction with stem cell therapy synergistically improves recovery from severe SCI. Furthermore, our results indicate that the effect of curcumin extends beyond its known anti-inflammatory properties to the regulation of stem cell proliferation.

Combined-Modality Therapy With Radiation and Chemotherapy for Elderly Patients With Glioblastoma in the Temozolomide Era: A National Cancer Database Analysis

IMPORTANCE The optimal management for elderly patients with glioblastoma (GBM) is controversial. Following maximal safe resection or biopsy, accepted treatment paradigms for elderly patients with GBM include combined-modality therapy (CMT) with both radiotherapy (RT) and chemotherapy (CT), RT alone, and CT alone. OBJECTIVE To evaluate the overall survival (OS) outcomes associated with RT, CT, and CMT for elderly patients with GBM in the modern temozolomide era. DESIGN, SETTING, AND PARTICIPANTS In this retrospective cohort study of a prospectively maintained, multi-institutional national cancer registry, the National Cancer Database was queried for elderly patients (≥65 years) with newly diagnosed GBM from January 1, 2005, through December 31, 2011, with complete data sets for RT, CT, tumor resection, Charlson-Deyo comorbidity scores, age, sex, and year of diagnosis. Data analysis was performed from October 2015 through December 2015. INTERVENTIONS Combined-modality therapy, RT, CT. MAIN OUTCOMES AND MEASURES Survival by treatment cohort was estimated using the Kaplan-Meier method and analyzed using the log rank test, univariate and multivariate Cox models, and propensity score-matched analyses. RESULTS A total of 16 717 patients (median [range] age, 73 [65-≥90 y]; 8870 [53%] male) were identified. The median OS by treatment was 9.0 (95% CI, 8.8-9.3) months with CMT (8435 patients), 4.7 (95% CI, 4.5-5.0) months with RT alone (1693 patients), 4.3 (95% CI, 4.0-4.7) months with CT alone (1018 patients), and 2.8 (95% CI, 2.8-2.9) months with no therapy (5571 patients) (P < .001). On multivariate analysis, CMT was superior to both CT alone (hazard ratio, 1.50 [95% CI, 1.40-1.60]; P < .001) and RT alone (hazard ratio, 1.47 [95% CI, 1.39-1.55]; P < .001), whereas no differences were observed between CT alone vs RT alone (P = .60). Propensity score-matched analyses redemonstrated improved OS with CMT over CT alone (P = .002) and RT alone (P < .001); no differences were observed between CT alone vs RT alone (P = .44). On subgroup analyses, a consistent OS advantage was observed with CMT over both CT alone and RT alone across each age stratification (65-69, 70-74, 75-79, and ≥80 years) and among patients treated with or without tumor resection (all P < .001). CONCLUSIONS AND RELEVANCE In this analysis of multimodality therapy for elderly patients with GBM, OS was superior with CMT compared with CT alone and RT alone. Survival was similar between CT alone and RT alone, and both CT alone and RT alone were superior to no therapy. This analysis supports the use of CMT for suitable elderly candidates.

The Supraorbital Keyhole Craniotomy through an Eyebrow Incision: Its Origins and Evolution

In the modern era of neurosurgery, the use of the operative microscope, rigid rod-lens endoscope, and neuronavigation has helped to overcome some of the previous limitations of surgery due to poor lighting and anatomic localization available to the surgeon. Over the last thirty years, the supraorbital craniotomy and subfrontal approach through an eyebrow incision have been developed and refined to play a legitimate role in the armamentarium of the modern skull base neurosurgeon. With careful patient selection, the supraorbital “keyhole” approach offers a less invasive but still efficacious approach to a number of lesions along the subfrontal corridor. Well over 1000 cases have been reported in the literature utilizing this approach establishing its safety and efficacy. This paper discusses the nuances of this approach, including the benefits and limitations of its use described through our technique, review of the literature, and case illustration.

Epilepsy surgery of the rolandic and immediate perirolandic cortex: Surgical outcome and prognostic factors

Herein we present a single‐center retrospective study of patients who underwent epilepsy surgery for seizures arising from the sensorimotor (rolandic) cortex. The goal was to find prognostic factors associated with better seizure outcome and to evaluate both surgical and neurologic outcomes.

Neuroendoscopic Resection of Intraventricular Tumors and Cysts through a Working Channel with a Variable Aspiration Tissue Resector: A Feasibility and Safety Study

Pure neuroendoscopic resection of intraventricular lesions through a burr hole is limited by the instrumentation that can be used with a working channel endoscope. We describe a safety and feasibility study of a variable aspiration tissue resector, for the resection of a variety of intraventricular lesions. Our initial experience using the variable aspiration tissue resector involved 16 patients with a variety of intraventricular tumors or cysts. Nine patients (56%) presented with obstructive hydrocephalus. Patient ages ranged from 20 to 88 years (mean 44.2). All patients were operated on through a frontal burr hole, using a working channel endoscope. A total of 4 tumors were resected in a gross total fashion and the remaining intraventricular lesions were subtotally resected. Fifteen of 16 patients had relief of their preoperative symptoms. The 9 patients who presented with obstructive hydrocephalus had restoration of cerebrospinal fluid flow though one required a ventriculoperitoneal shunt. Three patients required repeat endoscopic resections. Use of a variable aspiration tissue resector provides the ability to resect a variety of intraventricular lesions in a safe, controlled manner through a working channel endoscope. Larger intraventricular tumors continue to pose a challenge for complete removal of intraventricular lesions.

Cerebrospinal Fluid Leaks and Encephaloceles of Temporal Bone Origin: Nuances to Diagnosis and Management

OBJECTIVE Temporal bone encephalocele has become less common as the incidence of chronic mastoid infection and surgery for this condition has decreased. As a result, the diagnosis is often delayed, and the encephalocele is often an incidental finding. This situation can result in serious neurologic complications with patients presenting with cerebrospinal fluid leak and meningitis. We review the occurrence of, characteristics of, and repair experience with temporal encephaloceles from 2000-2012. METHODS We conducted a retrospective review of 32 patients undergoing combined mastoidectomy and middle cranial fossa craniotomy for the treatment of temporal encephalocele. RESULTS The diagnosis of temporal encephalocele was made in all patients using high-resolution temporal bone computed tomography and magnetic resonance imaging. At the time of diagnosis, 12 patients had confirmed cerebrospinal fluid leak; other common presenting symptoms included hearing loss and ear fullness. Tegmen defect was most commonly due to chronic otitis media (n = 14). Of these patients, 8 had undergone prior mastoidectomy, suggesting an iatrogenic cause. Other etiologies included radiation exposure, congenital defects, and spontaneous defects. Additionally, 2 patients presented with meningitis; 1 patient had serious neurologic deficits resulting from venous infarction. CONCLUSIONS The risk of severe neurologic complications after the herniation of intracranial contents through a tegmen defect necessitates prompt recognition and appropriate management. Computed tomography and magnetic resonance imaging aid in definitive diagnosis. A combined mastoid/middle fossa approach allows for sustainable repair with adequate exposure of defects and support of intracranial contents.

Recovery from spinal cord injury using naturally occurring antiinflammatory compound curcumin: laboratory investigation.

OBJECT Spinal cord injury (SCI) is a debilitating disease. Primary SCI results from direct injury to the spinal cord, whereas secondary injury is a side effect from subsequent edema and ischemia followed by activation of proinflammatory cytokines. These cytokines activate the prosurvival molecule nuclear factor-κB and generate obstacles in spinal cord reinnervation due to gliosis. Curcumin longa is an active compound found in turmeric, which acts as an antiinflammatory agent primarily by inhibiting nuclear factor-κB. Here, the authors study the effect of curcumin on SCI recovery. METHODS Fourteen female Sprague-Dawley rats underwent T9-10 laminectomy and spinal cord contusion using a weight-drop apparatus. Within 30 minutes after contusion and weekly thereafter, curcumin (60 mg/kg/ml body weight in dimethyl sulfoxide) or dimethyl sulfoxide (1 ml/kg body weight) was administered via percutaneous epidural injection at the injury site. Spinal cord injury recovery was assessed weekly by scoring hindlimb motor function. Animals were killed 6 weeks postcontusion for histopathological analysis of spinal cords and soleus muscle weight evaluation. RESULTS Curcumin-treated rats had improved motor function compared with controls starting from Week 1. Body weight gain significantly improved, correlating with improved Basso-Beattie-Bresnahan scores. Soleus muscle weight was greater in curcumin-treated rats than controls. Histopathological analysis validated these results with increased neural element mass with less gliosis at the contusion site in curcumin-treated rats than controls. CONCLUSIONS Epidural administration of curcumin resulted in improved recovery from SCI. This occurred with no adverse effects noted in experimental animals. Therefore, curcumin treatment may translate into a novel therapy for humans with SCI.

Development of Novel Patient-Derived Xenografts from Breast Cancer Brain Metastases

Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2+ and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain-homing cells derived from highly aggressive TN MDA-MB-231 and HER2+ BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression in vivo, their suitability to validate therapies for established brain metastasis remains limited. The goal of this study was to develop and characterize novel human brain metastasis breast cancer patient-derived xenografts (BM-PDXs) to study the biology of brain metastasis and to serve as tools for testing novel therapeutic approaches. We obtained freshly resected brain metastases from consenting donors with breast cancer. Tissue was immediately implanted in the mammary fat pad of female immunocompromised mice and expanded as BM-PDXs. Brain metastases from 3/4 (75%) TN, 1/1 (100%) estrogen receptor positive (ER+), and 5/9 (55.5%) HER2+ clinical subtypes were established as transplantable BM-PDXs. To facilitate tracking of metastatic dissemination using BM-PDXs, we labeled PDX-dissociated cells with EGFP-luciferase followed by reimplantation in mice, and generated a BM-derived cell line (F2-7). Immunohistologic analyses demonstrated that parental and labeled BM-PDXs retained expression of critical clinical markers such as ER, progesterone receptor, epidermal growth factor receptor, HER2, and the basal cell marker cytokeratin 5. Similarly, RNA sequencing analysis showed clustering of parental, labeled BM-PDXs and their corresponding cell line derivative. Intracardiac injection of dissociated cells from BM-E22-1, resulted in magnetic resonance imaging-detectable macrometastases in 4/8 (50%) and micrometastases (8/8) (100%) mice, suggesting that BM-PDXs remain capable of colonizing the brain at high frequencies. Brain metastases developed 8–12 weeks after ic injection, located to the brain parenchyma, grew around blood vessels, and elicited astroglia activation characteristic of breast cancer brain metastasis. These novel BM-PDXs represent heterogeneous and clinically relevant models to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings.