Stereotactic Radiosurgery for Vestibular Schwannoma in Neurofibromatosis Type 2: An International Multicenter Case Series of Response and Malignant Transformation Risk.

BACKGROUND: Vestibular schwannomas (VSs) related to neurofibromatosis type 2 (NF2) are challenging tumors. The increasing use of stereotactic radiosurgery (SRS) necessitates further investigations of its role and safety. OBJECTIVE: To evaluate tumor control, freedom from additional treatment (FFAT), serviceable hearing preservation, and radiation-related risks of patients with NF2 after SRS for VS. METHODS: We performed a retrospective study of 267 patients with NF2 (328 VSs) who underwent single-session SRS at 12 centers participating in the International Radiosurgery Research Foundation. The median patient age was 31 years (IQR, 21-45 years), and 52% were male. RESULTS: A total of 328 tumors underwent SRS during a median follow-up time of 59 months (IQR, 23-112 months). At 10 and 15 years, the tumor control rates were 77% (95% CI: 69%-84%) and 52% (95% CI: 40%-64%), respectively, and the FFAT rate were 85% (95% CI: 79%-90%) and 75% (95% CI: 65%-86%), respectively. At 5 and 10 years, the serviceable hearing preservation rates were 64% (95% CI: 55%-75%) and 35% (95% CI: 25%-54%), respectively. In the multivariate analysis, age (hazards ratio: 1.03 [95% CI: 1.01-1.05]; P = .02) and bilateral VSs (hazards ratio: 4.56 [95% CI: 1.05-19.78]; P = .04) were predictors for serviceable hearing loss. Neither radiation-induced tumors nor malignant transformation were encountered in this cohort. CONCLUSION: Although the absolute volumetric tumor progression rate was 48% at 15 years, the rate of FFAT related to VS was 75% at 15 years after SRS. None of the patients with NF2-related VS developed a new radiation-related neoplasm or malignant transformation after SRS.

Treatment of WHO Grade 2 Meningiomas With Stereotactic Radiosurgery: Identification of an Optimal Group for SRS Using RPA.

PURPOSE: This study assesses a large multi-institutional database to present the outcomes of World Health Organization grade 2 meningiomas treated with stereotactic radiosurgery (SRS). We also compare the 3-year progression-free survival (PFS) to that reported in the Radiation Therapy Oncology Group 0539 phase 2 cooperative group meningioma trial. METHODS AND MATERIALS: From an international, multicenter group, data were collected for grade 2 meningioma patients treated with SRS for demonstrable tumor from 1994 to 2019. Statistical methods used included the Kaplan-Meier method, Cox proportional hazards analysis, and recursive partitioning analysis. RESULTS: Two hundred thirty-three patients treated at 12 institutions were included. Patients presented at a median age of 60 years (range, 13-90), and many had at least 2 prior resections (30%) or radiation therapy (22%). Forty-eight percent of patients had prior gross total resection. At SRS, the median treatment volume was 6.1 cm3 (0.1-97.6). A median 15 Gy (10-30) was delivered to a median percent isodose of 50 (30-80), most commonly in 1 fraction (95%). A model was developed using recursive partitioning analysis, with one point attributed to age >50 years, treatment volume >11.5 cm3, and prior radiation therapy or multiple surgeries. The good-prognostic group (score, 0-1) had improved PFS (P < .005) and time to local failure (P < .005) relative to the poor-prognostic group (score, 2-3). Age >50 years (hazard ratio = 1.85 [95% confidence interval, 1.09-3.14]) and multiple prior surgeries (hazard ratio = 1.80 [1.09-2.99]) also portended reduced PFS in patients without prior radiation therapy. Two hundred eighteen of 233 patients in this study qualified for the high-risk group of Radiation Therapy Oncology Group 0539, and they demonstrated similar outcomes (3-year PFS: 53.9% vs 58.8%). The good-prognostic group of SRS patients demonstrated slightly improved outcomes (3-year PFS: 63.1% vs 58.8%). CONCLUSIONS: SRS should be considered in carefully selected patients with atypical meningiomas. We suggest the use of our good-prognostic group to optimize patient selection, and we strongly encourage the initiation of a clinical trial to prospectively validate these outcomes.

Stereotactic Radiosurgery for Atypical (World Health Organization II) and Anaplastic (World Health Organization III) Meningiomas: Results From a Multicenter, International Cohort Study.

BACKGROUND: Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described. OBJECTIVE: To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs. METHODS: An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model. RESULTS: A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P < .05) and a Ki-67 index > 15% (HR = 1.66, P < .03) negatively correlated with PFS. MMs (HR = 3.21, P < .05), increased age (HR = 1.04, P = .04), and reduced KPS (HR = 0.95, P = .04) were associated with shortened OS. Adjuvant versus salvage SRS did not impact PFS/OS. A shortened interval between surgery and SRS improved PFS for AMs (HR = 0.99, P = .02) on subgroup analysis. Radiation necrosis occurred in 34 (12.5%) patients. Five-year rates of repeat surgery/radiation were 33.8% and 60.4%, respectively. CONCLUSION: AM/MMs remain challenging tumors to treat. Elevated proliferative indices are associated with tumor recurrence, while MMs have worse survival. SRS can control AM/MMs in the short term, but the 5-yr PFS rates are low, underscoring the need for improved treatment options for these patients.

An autopsy report of basilar artery aneurysm flow diversion complicated by postoperative day 3 hemorrhage from vessel rupture.

A middle-aged patient presented with posterior circulation symptoms attributable to a large eccentric basilar trunk aneurysm. The planned treatment was flow diversion with loose coil packing which was successfully performed using a Pipeline Flex device deployed from the basilar to the left posterior cerebral artery. The complete procedure including live biplane fluoroscopy was digitally recorded. The patient had symptomatic improvement postoperatively and was discharged on day 1. The patient suffered a cardiac arrest on postoperative day 3 secondary to massive intraventricular and subarachnoid hemorrhage. An aneurysm rupture was suspected; however, postmortem examination showed an intact aneurysm sac. The hemorrhage was attributed to a small focal rent in the distal basilar artery next to an atheromatous plaque. The Pipeline device was visible through the rent. This is an autopsy report documenting an injury to the parent artery and not the aneurysm as a source of fatal delayed subarachnoid hemorrhage following flow diversion.

Rapid Development of Spinal Epidural Lipomatosis after Treatment of Metastatic Castration-Resistant Prostate Cancer with Second-Generation Androgen Receptor Antagonists.

BACKGROUND: Previous studies have described the association of spinal epidural lipomatosis with several conditions including chronic steroid therapy, Cushing's syndrome, obesity, Paget disease, and hypothyroidism. We present a report of rapid development of spinal epidural lipomatosis after treatment with second-generation anti-androgen therapy, a new strategy for treatment of metastatic castration-resistant prostate cancer that has been increasingly employed in the past few years. A comprehensive discussion of the underlying molecular networks involving androgen receptor blockage and adipocyte differentiation, as well as the clinical implications of such a phenomenon, are provided. CASE DESCRIPTION: We describe the clinical and radiological evolution of a 58-year-old male patient with metastatic prostate cancer, who developed new onset of rapidly progressing lumbosacral epidural lipomatosis with significant compression of the nerve roots of the cauda equina a few months after initiation of treatment with second-generation androgen receptor antagonists. CONCLUSIONS: The underlying pathophysiology of adipose tissue growth following the administration of anti-androgen therapy is discussed, with emphasis on both the canonical Wnt/ß-catenin pathway as well as in the Wnt-independent pathway involving direct activation of downstream transcription factors from the T-cell factor family by the androgen receptor. As second-generation androgen receptor antagonists have been increasingly used for treatment of castration-resistant stage metastatic prostate cancer, new onset of symptomatic epidural lipomatosis should be considered as a possible differential diagnosis, especially because the urinary symptoms of cauda equina compression may be improperly attributed to the primary prostate neoplasm.

An autopsy report of basilar artery aneurysm flow diversion complicated by postoperative day 3 hemorrhage from vessel rupture.

A middle-aged patient presented with posterior circulation symptoms attributable to a large eccentric basilar trunk aneurysm. The planned treatment was flow diversion with loose coil packing which was successfully performed using a Pipeline Flex device deployed from the basilar to the left posterior cerebral artery. The complete procedure including live biplane fluoroscopy was digitally recorded. The patient had symptomatic improvement postoperatively and was discharged on day 1. The patient suffered a cardiac arrest on postoperative day 3 secondary to massive intraventricular and subarachnoid hemorrhage. An aneurysm rupture was suspected; however, postmortem examination showed an intact aneurysm sac. The hemorrhage was attributed to a small focal rent in the distal basilar artery next to an atheromatous plaque. The Pipeline device was visible through the rent. This is an autopsy report documenting an injury to the parent artery and not the aneurysm as a source of fatal delayed subarachnoid hemorrhage following flow diversion.

Clinical Outcomes of Total Disc Replacement Versus Anterior Lumbar Interbody Fusion for Surgical Treatment of Lumbar Degenerative Disc Disease.

STUDY DESIGN: The authors performed a retrospective controlled study of patients diagnosed with lumbar degenerative disc disease who received surgical intervention (either total disc replacement [TDR]/Activ-L or anterior lumbar interbody fusion [ALIF]) at a single tertiary-care hospital from 2007-2010. OBJECTIVES: To investigate the clinical outcomes after TDR in comparison with ALIF for surgical treatment of lumbar degenerative disc disease (DDD). METHODS: Analyzed data included intra-operative blood loss, time to return to work, and clinical outcomes as evaluated through the Oswestry Disability Index (ODI) and the Visual Analog Scale (VAS) pain questionnaires pre-operatively and at 6 weeks, 3 months, 6 months, and 1 year postoperative follow-up. RESULTS: At the univariate analysis, patients submitted to TDR presented significantly lower VAS pain scores than patients who received ALIF starting at 6 weeks (P < .001) and continuing through one year postoperatively (P = .007). Patients submitted to TDR also presented significantly lower ODI disability scores at all time points. There was a significant difference in the number of days to return to work, with TDR patients returning to work on average 65 days sooner than ALIF patients (P = .011). There was no significant difference in the total blood loss between both groups. CONCLUSIONS: The results of this retrospective controlled study suggest that, in comparison with patients submitted to ALIF, patients submitted to TDR present quicker return to work, less back pain, and lower disability scores at 1 year follow-up.

Preclinical biomarker associations with both incident rheumatoid arthritis and its subsequent mortality: sex effects in a 41-year, community-based, case-control cohort study.

OBJECTIVES: To identify sex effects and preclinical serum biomarker associations with both incident rheumatoid arthritis (RA) and its subsequent mortality, using a 41-year, community-based, case-control cohort. METHODS: After cohort entry in 1974, incident RA cases (n=54) had clinical onsets between 1977 and 1994. Cohort control (CN) subjects were individually matched on entry to cases (4 CN:1 RA, n=216). All subjects were followed for survival from 1995 through 2015. Ranks (1-5) of preclinical z-scores within each set of 1 RA and 4 matched CN were analysed for associations with incident RA and mortality. Survival was evaluated using Cox proportional hazards models. RESULTS: Preclinical serum IgG RF z-score ranks associated with incident RA in 90 males (18 RA, 72 CN). Cigarette smoking, androstenedione, pregnenolone, and sIL-2Rα ranks associated with incident RA in 180 females (36 RA, 144 CN). Total percentile mortality was greater (p=0.003) in RA (70.4) vs. CN (49.9) and equivalently increased in female RA (69.4) vs. CN (49.3) and in male RA (72.2) vs. CN (43.1) subjects. Percentile respiratory-related CODs were greater (p=0.009) only in the female RA cases (16.7) vs. CN (3.5). Ranks of preclinical hsCRP (p=0.028) and sIL-2Rα (p=0.030) independently associated with 140 total deaths, as did sTNF-R1 (p=0.003) and hsCRP (p=0.005) with 50 CVD deaths. Latter biomarker association were significant in females. Therapy responses in 1995 significantly associated with subsequent mortality. CONCLUSIONS: Sex effects were important in preclinical biomarker associations with incident RA, total and CVD mortality as well as occurrence of respiratory deaths.

Successful Treatment of Symptomatic Intracranial Carotid Artery Stenosis Using a 24-mm Long Bare Metal Coronary Stent.

BACKGROUND: Intracranial arterial atherosclerosis represents a common cause of stroke. Despite aggressive and optimal medical management, many patients will unfortunately suffer additional cerebrovascular events. The role of endovascular intervention for intracranial atherosclerotic disease continues to be uncertain, particularly in regard to extensive, symptomatic stenosis. CASE DESCRIPTION: We present a case of a 42-year-old man with a complex medical history who presented with recurrent ischemic stroke in the ipsilateral hemisphere despite optimal medical management. Given the length of stenosis and the luminal size of the intracranial cavernous and petrous segments of the internal carotid artery, we used a bare metal coronary stent (4.0 mm × 24 mm). This represents one of the longest stents deployed for intracranial disease reported in the literature. CONCLUSIONS: This case illustrates that a long coronary stent might be successfully used to manage extensive intracranial lesions. We also review the efficacy of using 1 very long stent versus multiple overlapping stents, with reference to the coronary angiography literature.

The 'Lumbar Fusion Outcome Score' (LUFOS): a new practical and surgically oriented grading system for preoperative prediction of surgical outcomes after lumbar spinal fusion in patients with degenerative disc disease and refractory chronic axial low back pain.

In order to evaluate the predictive effect of non-invasive preoperative imaging methods on surgical outcomes of lumbar fusion for patients with degenerative disc disease (DDD) and refractory chronic axial low back pain (LBP), the authors conducted a retrospective review of 45 patients with DDD and refractory LBP submitted to anterior lumbar interbody fusion (ALIF) at a single center from 2007 to 2010. Surgical outcomes - as measured by Visual Analog Scale (VAS/back pain) and Oswestry Disability Index (ODI) - were evaluated pre-operatively and at 6 weeks, 3 months, 6 months, and 1 year post-operatively. Linear mixed-effects models were generated in order to identify possible preoperative imaging characteristics (including bone scan/99mTc scintigraphy increased endplate uptake, Modic endplate changes, and disc degeneration graded according to Pfirrmann classification) which may be predictive of long-term surgical outcomes . After controlling for confounders, a combined score, the Lumbar Fusion Outcome Score (LUFOS), was developed. The LUFOS grading system was able to stratify patients in two general groups (Non-surgical: LUFOS 0 and 1; Surgical: LUFOS 2 and 3) that presented significantly different surgical outcomes in terms of estimated marginal means of VAS/back pain (p = 0.001) and ODI (p = 0.006) beginning at 3 months and continuing up to 1 year of follow-up. In conclusion,  LUFOS has been devised as a new practical and surgically oriented grading system based on simple key parameters from non-invasive preoperative imaging exams (magnetic resonance imaging/MRI and bone scan/99mTc scintigraphy) which has been shown to be highly predictive of surgical outcomes of patients undergoing lumbar fusion for treatment for refractory chronic axial LBP.

Increased mortality of incident rheumatoid arthritis versus matched non-RA control subjects: a community-based long-term prospective cohort study.

OBJECTIVES: This study aimed to critically investigate all-cause and major-cause mortality of incident rheumatoid arthritis (RA) cases versus matched non-RA comparison (CN) subjects in a long-term prospective cohort. METHODS: Baseline 1974 cohort entry demographic and serum biomarker data on 54 incident RA patients and 216 matched CN subjects were related to their mortality from 1995 through 2015. Mortality of RA patients was also analysed by 3 categories of course responses to therapy assigned by the sole community rheumatologist in 1995 (19 good, 23 fair, and 12 limited). Cox proportional hazards regression models including baseline covariates were used to determine survival from all-causes, cardiovascular disease (CVD), respiratory-related, malignancies, and other causes of death (CODs). RESULTS: Total deaths occurred in 38 (70.4 percent) of 54 RA and 102 (47.7 percent) of 216 CN (p=0.003). Total mortality remained greater (p=0.011) in RA versus CN subjects after adjustment for baseline demographic covariates (HR= 1.66, 95% CI 1.12-2.46). Respiratory-related CODs were also greater (p=0.047) in RA versus CN (HR= 2.69, 95% CI 1.02-7.14) subjects. The RA patients' responses to therapy in 1995 significantly (p=0.004) predicted total mortality. Baseline serum immunological and steroid biomarkers independently predicted total, CVD, and other and unknown CODs. Pre-clinical (1974) ranked biomarker z-score values (1 = lowest, 5 = highest) within matched sets of 1 RA and 4 CN study subjects independently associated with mortality from 1995 through 2015, for both total (CRP, p=0.028 and sIL-2Rα, p=0.030) and CVD (CRP, p=0.005 and sTNF-R1, p=0.003) deaths. CONCLUSIONS: Total mortality and respiratory-related CODs were greater in incident RA versus CN subjects. The 35 RA cases who had fair or limited course responses to rheumatologist's therapy had greater mortality than their matched CN, whereas the 19 good RA responders had equivalent survival to CN subjects. The independent CRP and sTNF-R1 biomarker associations with CVD deaths were enhanced by a gradient of their dichotomous z-score values in survival models.

Successful outcome after endovascular thrombolysis for acute ischemic stroke with basis on perfusion-diffusion mismatch after 24 h of symptoms onset.

BACKGROUND: Although intravenous thrombolysis is the Food and Drug Administration-approved treatment for acute ischemic stroke (AIS) within 3 h, combined intravenous and intra-arterial thrombolysis with endovascular techniques may be able to extend this traditional time window. CASE DESCRIPTION: We present the clinical evolution of a 45-year-old male presenting with acute left hemiparesis. Magnetic resonance imaging revealed a small diffusion restriction at the right basal ganglia with perfusion compromise in the entire right middle cerebral artery (MCA) territory. Angiography revealed a complete occlusion of MCA at its M1 segment. The patient underwent endovascular mechanical thrombectomy with additional intra-arterial thrombolysis more than 24 hours after the onset of the initial symptoms and experienced complete vessel recanalization. At 1 year, the patient had global independence with minor residual motor impairment in the left arm. CONCLUSIONS: We report the case of a successful thrombolytic therapy following AIS performed more than 24 h after the initial symptoms based on the presence of a perfusion-diffusion mismatch. This report is expected to stimulate the development of future prospective studies with special focus on the role of perfusion-diffusion mismatch in patient selection for treatment of AIS, especially in those presenting outside the traditional time window.

Sexual Dimorphisms of Adrenal Steroids, Sex Hormones, and Immunological Biomarkers and Possible Risk Factors for Developing Rheumatoid Arthritis.

Innate immunity and immunological biomarkers are believed to be interrelated with sex hormones and other neuroendocrine factors. Sexual dimorphism mechanisms may be operating in certain rheumatic and inflammatory diseases which occur more frequently in women than men, as rheumatoid arthritis (RA). Less data have been available on altered interrelations of the combined neuroendocrine and immune (NEI) systems as risk factors for development of certain diseases. In this study, serological interrelations of NEI biomarkers are analyzed before symptomatic onset of RA (pre-RA) versus control (CN) subjects, stratified by sex. Sexual dimorphism was found in serum levels of acute serum amyloid A (ASAA), soluble interleukin-2 receptor alpha (sIL-2Rα), and soluble tumor necrosis factor receptor 1 (sTNF-R1). Multiple steroidal and hormonal (neuroendocrine) factors also showed highly (p < 0.001) significant sexual dimorphism in their assayed values, but less for cortisol (p = 0.012), and not for 17-hydroxyprogesterone (p = 0.176). After stratification by sex and risk of developing RA, differential NEI correlational patterns were observed in the interplay of the NEI systems between the pre-RA and CN groups, which deserve further investigation.

Acute Spinal Subdural Hematoma after Vertebroplasty: A Case Report Emphasizing the Possible Etiologic Role of Venous Congestion.

Study Design Case report and literature review. Objective Spinal subdural hematomas are rare events that often progress with severe neurologic deficits. Although there have been several case reports in the literature of spontaneous spinal subdural hematomas in the setting of anticoagulation, antiplatelet therapy, or coagulation disorders, the exact pathophysiology of such phenomena remains obscure. Methods We present the first report of a subdural hematoma after a percutaneous vertebroplasty and provide a comprehensive review on the anatomy of venous drainage of the vertebral bodies with emphasis on the possible effects of venous congestion caused by cement obstruction. Results Because the subdural hematoma occurred in the absence of major cement extravasation to the spinal canal and two levels above the site of the vertebroplasty, we discuss the possible role of venous congestion as the main etiologic factor leading to rupture of the fragile, valveless radiculomedullary veins into the subdural space. Conclusions The reported case supports a possible new pathophysiological scheme for the development of spinal subdural hematoma in which venous congestion plays a pivotal etiologic role. The reported findings suggests that future anatomical and histologic studies investigating the response of the radiculomedullary veins to congestive venous hypertension may shed new light into the pathophysiology of spinal subdural hematomas.

Surgical challenges in the management of cervical kyphotic deformity in patients with severe osteoporosis: an illustrative case of a patient with Hajdu-Cheney syndrome.

PURPOSE: No standard strategy exists for the management of cervical kyphotic deformity in patients with severe osteoporosis. In fact, in such subpopulation, standard algorithms commonly used in patients with normal bone mineral density may not be applicable. In this Grand Rounds, the authors present a challenging case of a patient with Hajdu-Cheney syndrome, a rare disorder of bone metabolism induced by a Notch-2 mutation, who presented with cervical kyphotic deformity and severe osteoporosis. METHODS: A 65-year-old female patient with a previous diagnosis of Hajdu-Cheney syndrome presented with cervical myelopathy and cervical kyphotic deformity. The initial MRi demonstrated multilevel cervical canal stenosis. The CT-scan also revealed marked spondylolisthesis of C6 over C7 as well as numerous laminar and pedicle fractures, resulting in a cervical kyphosis of approximately 50 degrees. RESULTS: The patient was submitted to 360-degree decompression and fusion of the cervical spine consisting of a staged C6 anterior corpectomy and multilevel microdiscectomies with wide opening of the posterior longitudinal ligament in order to provide a satisfactory release of anterior spinal structures, followed by 24 h of cervical halo-traction, a second anterior approach for bone graft implantation in the site of the corpectomy as well as insertion of allografts and completion of the ACDF C2-T1 and plating, and, finally, a posterior C2-T3 pedicle screw instrumentation using intra-operative CT-scan (O-arm) navigation guidance. CONCLUSIONS: This case illustrates some intra-operative nuances as well as specific surgical recommendations for cervical deformity surgery in patients with severe osteoporosis, such as avoidance of Caspar pins for interbody distraction, use of intra-operative fluoroscopy for achievement of bicortical purchase of anterior cervical screws and placement of pedicle screws during posterior instrumentation. Moreover, such illustrative case demonstrates that, in the subpopulation of patients with severe osteoporosis, it may be possible to successfully apply cervical distraction after an isolated anterior approach with a satisfactory improvement in the cervical alignment, possibly avoiding more laborious 540-degree approaches such as the previously described back-front-back or front-back-front surgical algorithms.

The effects of alternating electric fields in glioblastoma: current evidence on therapeutic mechanisms and clinical outcomes.

Glioblastoma is both the most common and most lethal primary CNS malignancy in adults, accounting for 45.6% of all malignant CNS tumors, with a 5-year survival rate of only 5.0%, despite the utilization of multimodal therapy including resection, chemotherapy, and radiation. Currently available treatment options for glioblastoma often remain limited, offering brief periods of improved survival, but with substantial side effects. As such, improvements in current treatment strategies or, more likely, the implementation of novel strategies altogether are warranted. In this topic review, the authors provide a comprehensive review on the potential of alternating electric fields (AEFs) in the treatment of glioblastoma. Alternating electric fields-also known as tumor-treating fields (TTFs)-represent an entirely original therapeutic modality with preliminary studies suggesting comparable, and at times improved, efficacy to standard chemotherapeutic agents in the treatment of recurrent glioblastoma. A recent multicenter, Phase III, randomized clinical trial comparing NovoTTF-100A monotherapy to physician's best choice chemotherapy in patients with recurrent glioblastoma revealed that AEFs have similar efficacy to standard chemotherapeutic agents with a more favorable side-effects profile and improved quality of life. In particular, AEFs were shown to have limited systemic adverse effects, with the most common side effect being contact dermatitis on the scalp at the sites of transducer placement. This study prompted FDA approval of the NovoTTF-100A system in April 2011 as a standalone therapy for treatment of recurrent glioblastoma refractory to surgical and radiation treatment. In addition to discussing the available clinical evidence regarding the utilization of AEFs in glioblastoma, this article provides essential information regarding the supposed therapeutic mechanism as well as modes of potential tumor resistance to such novel therapy, delineating future perspectives regarding basic science research on the issue.

"Extremely minimally invasive": recent advances in nanotechnology research and future applications in neurosurgery.

The term "nanotechnology" refers to the development of materials and devices that have been designed with specific properties at the nanometer scale (10(-9) m), usually being less than 100 nm in size. Recent advances in nanotechnology have promised to enable visualization and intervention at the subcellular level, and its incorporation to future medical therapeutics is expected to bring new avenues for molecular imaging, targeted drug delivery, and personalized interventions. Although the central nervous system presents unique challenges to the implementation of new therapeutic strategies involving nanotechnology (such as the heterogeneous molecular environment of different CNS regions, the existence of multiple processing centers with different cytoarchitecture, and the presence of the blood-brain barrier), numerous studies have demonstrated that the incorporation of nanotechnology resources into the armamentarium of neurosurgery may lead to breakthrough advances in the near future. In this article, the authors present a critical review on the current 'state-of-the-art' of basic research in nanotechnology with special attention to those issues which present the greatest potential to generate major therapeutic progresses in the neurosurgical field, including nanoelectromechanical systems, nano-scaffolds for neural regeneration, sutureless anastomosis, molecular imaging, targeted drug delivery, and theranostic strategies.

Therapeutic options for the management of pancreatic cancer.

Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatments are desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient's life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.

Do women with premenopausal-onset rheumatoid arthritis have relative insufficiency or imbalance of adrenocortical steroids?

Adrenocortical steroids may influence susceptibility to rheumatoid arthritis (RA). Serum levels of adrenocortical steroids in female RA patients not previously treated with glucocorticoids were reviewed in this paper, as were controlled cohort studies of predisease (pre-RA) and control (CN) women. Serum dehydroepiandrosterone sulfate (DHEAS) levels were lower in most reports of premenopausal-onset RA patients not treated with glucocorticoids and in the baseline levels in one cohort study of pre-RA females compared with CN subjects. The pre-RA versus CN cohort difference was confirmed in an independent laboratory. Basal DHEAS and cortisol levels correlated oppositely in pre-RA versus CN women, suggesting relative adrenocortical androgenic insufficiency in case subjects. Clinical observations of lower androstenedione levels in premenopausal RA patients were also reported in pre-RA versus CN subjects who had lower DHEAS and cortisol values. In summary, a minority of premenopausal-onset RA females had decreased adrenocortical androgenic steroid levels and exhibited an adrenal androgen-to-cortisol steroid imbalance.

Sustained long-term complete regression of a giant cell tumor of the spine after treatment with denosumab.

BACKGROUND CONTEXT: Although giant cell tumors (GCTs) are histologically benign, they may become locally aggressive bone tumors. As these lesions tend to respond poorly to radio- and chemotherapy, currently the standard surgical paradigm for the treatment of spinal GCTs involves en bloc surgical resection. Denosumab is a newly developed monoclonal antibody designed to inhibit the receptor activator of nuclear factor kappa-B ligand (RANKL) which has already been demonstrated to induce marked radiographic responses on GCTs of the appendicular skeleton. Nevertheless, the role of denosumab in the treatment algorithm of GCTs of the spine has not yet been defined. PURPOSE: To describe the first case of sustained long-term complete clinical and radiographic regression of a GCT of the spine after treatment with the new RANKL antibody denosumab. STUDY DESIGN: Case report and literature review. METHODS: The authors describe the case of 22-year-old female patient, harboring a GCT involving the C2 vertebral body and odontoid process, who was treated in monotherapy with denosumab, resulting in complete long-term clinical and radiographic tumor remission. RESULTS: There were no major side effects associated with the long-term pharmacological treatment with denosumab. From the clinical standpoint, the patient demonstrated complete remission of the disease while under treatment. The 16-month radiographic follow-up demonstrated complete disappearance of the osteolytic process and intense new cortical bone formation with restoration of the bone integrity of the C2 vertebral body. CONCLUSIONS: This is the first report of sustained long-term complete clinical and radiographic regression of a GCT of the spine after treatment with the new RANKL antibody denosumab. Although future long-term follow-up studies are still necessary to establish important key points regarding the best therapeutic protocol with such a new drug (such as the optimal time frame to keep the patient under treatment), denosumab promises to bring major changes to the current therapeutic paradigm for GCTs of the spine, which, up to now, has strongly relied on en bloc surgical resection.