Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop.

Lysosomes have a central role in cellular catabolism, trafficking, and processing of foreign particles. Accumulation of endogenous and exogenous materials in lysosomes represents a common finding in nonclinical toxicity studies. Histologically, these accumulations often lack distinctive features indicative of lysosomal or cellular dysfunction, making it difficult to consistently interpret and assign adverse dose levels. To help address this issue, the European Society of Toxicologic Pathology organized a workshop where representative types of lysosomal accumulation induced by pharmaceuticals and environmental chemicals were presented and discussed. The expert working group agreed that the diversity of lysosomal accumulations requires a case-by-case weight-of-evidence approach and outlined several factors to consider in the adversity assessment, including location and type of cell affected, lysosomal contents, severity of the accumulation, and related pathological effects as evidence of cellular or organ dysfunction. Lysosomal accumulations associated with cytotoxicity, inflammation, or fibrosis were generally considered to be adverse, while those found in isolation (without morphologic or functional consequences) were not. Workshop examples highlighted the importance of thoroughly characterizing the biological context of lysosomal effects, including mechanistic data and functional in vitro readouts if available. The information provided here should facilitate greater consistency and transparency in the interpretation of lysosomal effects.

Factors associated with acute-phase response of bisphosphonate-naïve or pretreated women with osteoporosis receiving an intravenous first dose of zoledronate or ibandronate.

A first intravenous dose of bisphosphonates may be associated with an acute-phase response (APR). In bisphosphonate-naïve women with postmenopausal osteoporosis, the characteristics and frequency of APR may differ by compound. Prior bisphosphonate exposure was predictive of APR risk and severity. INTRODUCTION: Intravenous (IV) administration of bisphosphonates (BP), such as zoledronate (ZOL) and ibandronate (IBN), may be associated with an APR. The characteristics of APR may differ by compound. The aim of the present study was to evaluate the characteristics of APR (rates, signs and symptoms, severity), in the absence of any preventive measure, after a first IV application of ZOL or IBN in patients naïve or previously exposed to BP in a real-world clinical setting. METHODS: This is an open-label prospective exploratory study with two cohorts of consecutive postmenopausal women with osteoporosis treated with either IV ZOL or IBN at the Department of Osteoporosis of the University Hospital of Berne, Switzerland. RESULTS: Intravenous BP was administered to 725 women (411 ZOL and 314 IBN). Prior oral or IV BP use was less frequent in the ZOL group (61.8 vs. 71.7%, p = 0.005). In total, 301 women (41.5%) reported the presence of one or more signs or symptoms of APR with rates for ZOL and IBN of 47.7 and 33.4%, respectively (p < 0.001). Corresponding APR rates in the subgroup of BP-naïve patients were 55.6 and 32.4%, respectively (p < 0.001). The leading APR clinical sign was the presence of post-dose myalgia or arthralgia (68.1%). Prior BP exposure was predictive of both APR risk and severity, and lower serum 25-hydroxy vitamin D (25(OH)D) levels were possibly predictive of severity. CONCLUSIONS: In a real-world setting, APR rates with ZOL and IBN may be higher than reported in randomised controlled trials and may differ by compound, prior BP exposure, and serum 25(OH)D levels.

Rebound-associated vertebral fractures after discontinuation of denosumab-from clinic and biomechanics.

UNLABELLED: Rebound-associated vertebral fractures may follow treatment discontinuation of highly potent reversible bone antiresorptives, resulting from the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone. INTRODUCTION: The purposes of this study are to characterize rebound-associated vertebral fractures following the discontinuation of a highly potent reversible antiresorptive therapy based on clinical observation and propose a pathophysiological rationale. METHODS: This study is a case report of multiple vertebral fractures early after discontinuation of denosumab therapy in a patient with hormone receptor-positive non-metastatic breast cancer treated with an aromatase inhibitor. RESULTS: Discontinuation of highly potent reversible bone antiresorptives such as denosumab may expose patients to an increased fracture risk due to the joined effects of absent microdamage repair during therapy followed by synchronous excess activation of multiple bone remodelling units at the time of loss-of-effect. We suggest the term rebound-associated vertebral fractures (RVF) for this phenomenon characterized by the presence of multiple new clinical vertebral fractures, associated with either no or low trauma, in a context consistent with the presence of high bone turnover and rapid loss of lumbar spine bone mineral density (BMD) occurring within 3 to 12 months after discontinuation (loss-of-effect) of a reversible antiresorptive therapy in the absence of secondary causes of bone loss or fractures. Unlike atypical femoral fractures that emerge from failure of microdamage repair in cortical bone with long-term antiresorptive treatment, RVF originate from the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone triggered by the discontinuation of highly potent reversible antiresorptives. CONCLUSIONS: Studies are urgently needed to i) prove the underlying pathophysiological processes suggested above, ii) establish the predictive criteria exposing patients to an increased risk of RVF, and iii) determine appropriate treatment regimens to be applied in such patients.

Super-cooled and amorphous lipid-based colloidal dispersions for the delivery of phytosterols.

Super-cooled and amorphous lipid-based colloids are highly desirable delivery systems because of their ability to encapsulate compounds in a soluble or in a non-crystalline state. In this study, we demonstrate the preparation and characterization of super-cooled and amorphous lipid-based nanoscale colloidal dispersions containing high concentrations of phytosterols (PSs). PSs are highly hydrophobic natural bioactive compounds that are known to significantly reduce blood cholesterol levels in humans, but are insoluble in water and are poorly soluble in common lipids such as triacylglycerols (TAGs). Using the ultrahigh pressure homogenization of pre-heated dispersions, followed by temperature quenching, colloidal dispersions with varying concentrations of PSs in the lipid phase are prepared. Long and medium chain TAGs in combination with a non-ionic surfactant are used. The particle size, morphology and stability are analysed by dynamic and static light scattering, electron microscopy, and X-ray diffraction. Rapid temperature quenching enables the formation of stable colloidal dispersions of 10 wt% PSs, more than five times the equilibrium solubility at room temperature. Super-cooled emulsions are formed using liquid TAG, whereas amorphous particles are formed in the case of solid TAG. In both cases, the complete suppression of the crystallization of both PSs and lipids is observed due to the nanoscale confinement. The colloidal dispersions are stable for at least four months. The insights of this work will help understand the colloid formation and particle morphology control in the development of delivery systems for hydrophobic bio-actives such as drugs, cosmeceuticals, nutraceuticals, nutritional and agricultural nanoscale formulations.

Smart stylet: the development and use of a bedside external ventricular drain image-guidance system.

BACKGROUND: Placement accuracy of ventriculostomy catheters is reported in a wide and variable range. Development of an efficient image-guidance system may improve physician performance and patient safety. OBJECTIVE: We evaluate the prototype of Smart Stylet, a new electromagnetic image-guidance system for use during bedside ventriculostomy. METHODS: Accuracy of the Smart Stylet system was assessed. System operators were evaluated for their ability to successfully target the ipsilateral frontal horn in a phantom model. RESULTS: Target registration error across 15 intracranial targets ranged from 1.3 to 4.6 mm (mean 3.1 mm). Using Smart Stylet guidance, a test operator successfully passed a ventriculostomy catheter to a shifted ipsilateral frontal horn 20/20 (100%) times from the frontal approach in a skull phantom. Without Smart Stylet guidance, the operator was successful 4/10 (40%) times from the right frontal approach and 6/10 (60%) times from the left frontal approach. In a separate experiment, resident operators were successful 2/4 (50%) times when targeting the shifted ipsilateral frontal horn with Smart Stylet guidance and 0/4 (0%) times without image guidance using a skull phantom. CONCLUSIONS: Smart Stylet may improve the ability to successfully target the ventricles during frontal ventriculostomy.

Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study.

UNLABELLED: Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug. INTRODUCTION: The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1-34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis. METHODS: Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N = 65) or quarterly intravenous IBN (N = 122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared. RESULTS: Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9 ± 7.4 years, body mass index 23.8 ± 3.8 kg/m(2), BMD L1-L4 0.741 ± 0.100 g/cm(2), and TBS 1.208 ± 0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 % ± 6.3 vs. +2.9 % ± 3.3 and +4.3 % ± 6.6 vs. +0.3 % ± 4.1, respectively; P < 0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r (2) = 0.04) with no correlation between the changes in BMD and TBS over 24 months. CONCLUSIONS: In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.

Cerebral capillary telangiectasias: a meta-analysis and review of the literature.

As a result of their presumed benign natural history, cerebral capillary telangiectasias (CCTs) are infrequently addressed in the neurosurgical literature. We performed a comprehensive review of CCTs via the PubMed database to synthesize overall epidemiological, radiographic, natural history, and treatment results. Across ten series with 203 patients, mean age was 47, and 45 % were male [95 % confidence interval (CI), 0.30-0.65]. Notably, 78 % of CCTs were in the pons (95 % CI, 0.58-1.0). Six percent of CCTs were symptomatic. Across five radiographic series, all lesions enhanced after gadolinium, and all were hypointense on gradient echo sequences. Thirty-three percent were hypointense on T1-weighted pre-contrast imaging (95 % CI, 0.2-0.51), 49 % were hyperintense on T2-weighted imaging (95 % CI, 0.31-0.72), and 74 % were hypointense on diffusion-weighted imaging (95 % CI, 0.5-1.0). Notably, 37 % were associated with a prominent draining vein (95 % CI, 0.21-0.6), and 11 % with a developmental venous anomaly (95 % CI, 0.04-0.25). Across four observational studies with 47 patients, there was no observed change in lesion morphology or hemorrhage in 65.7 patient-years of follow-up. Although the vast majority of CCTs are managed conservatively, we found ten cases of patients treated with surgical excision. We confirm that CCTs are a benevolent entity with a predilection for the pons. They have distinctive radiographic features including their lack of mass effect, consistent enhancement on T1-weighted sequences and hypointensity on gradient echo sequences, and common isointensity on pre-contrast T1-weighted and T2-weighted images. Management for these lesions has been nonoperative in almost all cases.

Factors associated with external ventricular drain placement accuracy: data from an electronic health record repository.

BACKGROUND: We evaluated external ventricular drain placement for factors associated with placement accuracy. Data were acquired using an electronic health record data requisition tool. METHOD: Medical records of all patients who underwent ventriculostomy from 2003 to 2010 were identified and evaluated. Patient demographics, diagnosis, type of guidance and number of catheter passes were searched for and recorded. Post-procedural hemorrhage and/or infection were identified. A grading scale was used to classify accuracy of catheter placements. A multiple logistic regression model was developed to assess features associated with accurate catheter placement. RESULTS: One hundred nine patients who underwent 111 ventriculostomies from 2003 to 2010 were identified. Patient diagnoses were classified into vascular (63 %), tumor (21 %), trauma (14 %), and cyst (2 %). Procedures were performed freehand in 90 (81 %), with the Ghajar guide in 17 (15 %), and with image guidance in 4 (4 %) patients. Eighty-eight (79 %) catheters were placed in the correct location. Trauma patients were more likely to have catheters misplaced (p = 0.007) whereas patients in other diagnostic categories were not significantly associated with misplaced catheters. Post-procedural hemorrhage was noted in 2 (1.8 %) patients on post-procedural imaging studies. Five (4.5 %) definite and 6 (5.4 %) suspected infections were identified. CONCLUSIONS: External ventricular drain placement can be performed accurately in most patients. Patients with trauma are more likely to have catheters misplaced. Further development is required to identify and evaluate procedure outcomes using an electronic health record repository.

Developments in nanostructured LiMPO4 (M = Fe, Co, Ni, Mn) composites based on three dimensional carbon architecture.

Nanostructured materials lie at the heart of fundamental advances in efficient energy storage and/or conversion, in which surface processes and transport kinetics play determining roles. This review describes recent developments in the synthesis and characterization of composites which consist of lithium metal phosphates (LiMPO(4), M = Fe, Co, Ni, Mn) coated on nanostructured carbon architectures (unordered and ordered carbon nanotubes, amorphous carbon, carbon foams). The major goal of this review is to highlight new progress in using different three dimensional nanostructured carbon architectures as support for the phosphate based cathode materials (e.g.: LiFePO(4), LiCoPO(4)) of high electronic conductivity to develop lithium batteries with high energy density, high rate capability and excellent cycling stability resulting from their huge surface area and short distance for mass and charge transport.

Comparative trends in hospitalizations for osteoporotic fractures and other frequent diseases between 2000 and 2008.

UNLABELLED: In Switzerland, the number, incidence, and cost of acute hospitalizations for major osteoporotic fractures (MOF) and major cardiovascular events (MCE) increased in both women and men between 2000 and 2008, although the mean length of stay (LOS) was significantly reduced. Similar trend patterns were observed for hip fractures and strokes (decrease) and nonhip fractures and acute myocardial infarctions (increase). INTRODUCTION: The purpose of this study was to compare the trends and epidemiological characteristics of hospitalizations for MOF and other frequent diseases between years 2000 and 2008 in Switzerland. METHODS: Trends in the number, age-standardized incidence, mean LOS, and cost of hospitalized MOF and MCE (acute myocardial infarction, stroke, and heart failure) were compared in women and men aged ≥ 45 years, based on data from the Swiss Federal Statistical Office. RESULTS: Between 2000 and 2008, the incidence of acute hospitalizations for MOF increased by 3.4% in women and 0.3% in men. In both sexes, a significant decrease in hip fractures (-15.0% and -11.0%) was compensated by a concomitant, significant increase in nonhip fractures (+24.8% and +13.8%). Similarly, the incidence of acute hospitalizations for MCE increased by 4.4% in women and 8.2% in men, as an aggregated result from significantly increasing acute myocardial infarctions and significantly decreasing strokes. While the mean LOS in the acute inpatient setting decreased almost linearly between years 2000 and 2008 in all indications, the inpatient costs increased significantly (p < 0.001) for MOF (+30.1% and +42.7%) and MCE (+22.6% and +47.1%) in women and men, respectively. CONCLUSIONS: Between years 2000 and 2008, the burden of hospitalized osteoporotic fractures to the Swiss healthcare system has continued to increase in both sexes. In women, this burden was significantly higher than that of MCE and the gap widened over time.

Vertically aligned multiwalled carbon nanotubes for pressure, tactile and vibration sensing.

We report a simple method for the micro-nano integration of flexible, vertically aligned multiwalled CNT arrays sandwiched between a top and bottom carbon layer via a porous alumina (Al(2)O(3)) template approach. The electromechanical properties of the flexible CNT arrays have been investigated under mechanical stress conditions. First experiments show highly sensitive piezoresistive sensors with a resistance decrease of up to ∼35% and a spatial resolution of <1 mm. The results indicate that these CNT structures can be utilized for tactile sensing components. They also confirm the feasibility of accessing and utilizing nanoscopic CNT bundles via lithographic processing. The method involves room-temperature processing steps and standard microfabrication techniques.

Stereotactic radiosurgery for cerebral dural arteriovenous fistulas.

OBJECT: Given the feasibility of curative surgical and endovascular therapy for cerebral dural arteriovenous fistulas (DAVFs), there is a relative paucity of radiosurgical series for these lesions as compared with their arteriovenous malformation counterparts. METHODS: The authors reviewed records of 56 patients with 70 cerebral DAVFs treated at their institution over the past 6 years. Ten DAVFs (14%) in 9 patients were treated with stereotactic radiosurgery (SRS), with follow-up obtained for 8 patients with 9 DAVFs. They combined their results with those obtained from a comprehensive review of the literature, focusing on obliteration rates, post-SRS hemorrhage rates, and other complications. RESULTS: In the authors' group of 9 DAVFs, angiographic obliteration was seen in 8 cases (89%), and no post-SRS hemorrhage or complications were observed after a mean follow-up of 2.9 years. Combining the results in these cases with data obtained from their review of the literature, they found 558 DAVFs treated with SRS across 14 series. The overall obliteration rate was 71%; transient worsening occurred in 9.1% of patients, permanent worsening in 2.4% (including 1 death, 0.2% of cases), and post-SRS hemorrhage occurred in 1.6% of cases (4.8% of those with cortical venous drainage [CVD]). The obliteration rate for cavernous DAVFs was 84%, whereas the rates for transversesigmoid and for tentorial DAVFs were 58% and 59%, respectively (adjusted p values, p(cav,TS) = 1.98 × 10(-4), p(cav,tent) = 0.032). Obliteration rates were greater for DAVFs without CVD (80%, compared with 60% for those with CVD, p = 7.59 × 10(-4)). Both transient worsening and permanent worsening were less common in patients without CVD than in those with CVD (3.4% vs 7.3% for transient worsening and 0.9% vs 2.4% for permanent worsening). CONCLUSIONS: Stereotactic radiosurgery with or without adjunctive embolization is an effective therapy for DAVFs that are not amenable to surgical or endovascular monotherapy. It is best suited for lesions without CVD and for cavernous DAVFs.

Patterns in neurosurgical adverse events and proposed strategies for reduction.

Neurosurgery is a high-risk specialty currently undertaking the pursuit of systematic approaches to reducing risk and to measuring and improving outcomes. The authors performed a review of patterns and frequencies of adverse events in neurosurgery as background for future efforts directed at the improvement of quality and safety in neurosurgery. They found 6 categories of contributory factors in neurosurgical adverse events, categorizing the events as influenced by issues in surgical technique, perioperative medical management, use of and adherence to protocols, preoperative optimization, technology, and communication. There was a wide distribution of reported occurrence rates for many of the adverse events, in part due to the absence of definitive literature in this area and to the lack of standardized reporting systems. On the basis of their analysis, the authors identified 5 priority recommendations for improving outcomes for neurosurgical patients at a population level: 1) development and implementation of a national registry for outcome data and monitoring; 2) full integration of the WHO Surgical Safety Checklist into the operating room workflow, which improves fundamental aspects of surgical care such as adherence to antibiotic protocols and communication within surgical teams; and 3-5) activity by neurosurgical societies to drive increased standardization for the safety of specialized equipment used by neurosurgeons (3), more widespread regionalization and/or subspecialization (4), and establishment of data-driven guidelines and protocols (5). The fraction of adverse events that might be avoided if proposed strategies to improve practice and decrease variability are fully adopted remains to be determined. The authors hope that this consolidation of what is currently known and practiced in neurosurgery, the application of relevant advances in other fields, and attention to proposed strategies will serve as a basis for informed and concerted efforts to improve outcomes and patient safety in neurosurgery.

Neurosurgery residency and fellowship education in the United States: 2 decades of system development by the One Neurosurgery Summit organizations.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

Fracture hospitalizations between years 2000 and 2007 in Switzerland: a trend analysis.

UNLABELLED: In Switzerland, the total number and incidence of hospitalizations for major osteoporotic fractures increased between years 2000 and 2007, while hospitalizations due to hip fracture decreased. The cost impact of shorter hospital stays was offset by the increasing cost per day of hospitalization. INTRODUCTION: The aim of the study was to establish the trends and epidemiological characteristics of hospitalizations for major osteoporotic fractures (MOF) between years 2000 and 2007 in Switzerland. METHODS: Sex- and age-specific trends in the number and crude and age-standardized incidences of hospitalized MOF (hip, clinical spine, distal radius, and proximal humerus) in women and men aged ≥45 years were analyzed, together with the number of hospital days and cost of hospitalization, based on data from the Swiss Federal Statistical Office hospital database and population statistics. RESULTS: Between 2000 and 2007, the absolute number of hospitalizations for MOF increased by 15.9% in women and 20.0% in men, mainly due to an increased number of non-hip fractures (+37.7% in women and +39.7% in men). Hospitalizations for hip fractures were comparatively stable (-1.8% in women and +3.3% in men). In a rapidly aging population, in which the number of individuals aged ≥45 years grew by 11.1% (women) and 14.6% (men) over the study period, the crude and age-standardized incidences of hospitalizations decreased for hip fractures and increased for non-hip MOF, both in women and men. The length of hospital stay decreased for all MOF in women and men, the cost impact of which was offset by an increase in the daily costs of hospitalization. CONCLUSIONS: Between years 2000 and 2007, hospitalizations for MOF continued to increase in Switzerland, driven by an increasing number and incidence of hospitalizations for non-hip fractures, although the incidence of hip fractures has declined.

Food system development pathways for healthy, nature-positive and inclusive food systems.

Sustainable food systems require the integration of and alignment between recommendations for food and land use practices, as well as an understanding of the political economy context and identification of entry points for change. We propose a food systems transformation framework that takes these elements into account and links long-term goals with short-term measures and policies, ultimately guiding the decomposition of transformation pathways into concrete steps. Taking the transition to healthier and more sustainable diets as an example, we underscore the centrality of social inclusion to the food systems transformation debate.

All-optical steering of laser-wakefield-accelerated electron beams.

We investigate the influence of a tilted laser-pulse-intensity front on laser-wakefield acceleration. Such asymmetric light pulses may be exploited to obtain control over the electron-bunch-pointing direction and in our case allowed for reproducible electron-beam steering in an all-optical way within an 8 mrad opening window with respect to the initial laser axis. We also discovered evidence of collective electron-betatron oscillations due to off-axis electron injection into the wakefield induced by a pulse-front tilt. These findings are supported by 3D particle-in-cell simulations.

Metastatic gliosarcoma with a unique presentation and progression: case report and review of the literature.

A 51-year-old right-handed woman initially presented with generalized tonic-clonic seizures. MRI showed abnormal signal hyperintensity of the right temporal lobe that was thought to be consistent with ischemic stroke. Three years later, she developed an intensely enhancing centrally necrotic tumor in the right temporal-parietal lobes. A craniotomy was performed with gross total resection of the tumor followed by chemotherapy and radiation treatments. Histological examination demonstrated a gliosarcoma. A year later, she had a recurrence of the intra-axial gliosarcoma requiring a second craniotomy for tumor resection and placement of Gliadel wafers. Postoperatively, she developed plural effusions. A pulmonary workup revealed lung lesions that were biopsied and found to be gliosarcoma. After the second surgery, she underwent pleurodesis and one cycle of modified mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy, but died 5 months later from progression of the lung metastases. There are fewer than 20 reported cases of extracranial metastases of gliosarcoma. This is the first report of gliosarcoma with prolonged survival (over 2 years) and death from non-CNS metastatic gliosarcoma.

Intramedullary spinal cord cavernous malformations.

Although originally the subject of rare case reports, intramedullary spinal cord cavernous malformations (CMs) have recently surfaced in an increasing number of case series and natural history reports in the literature. The authors reviewed 27 publications with 352 patients to consolidate modern epidemiological, natural history, and clinical and surgical data to facilitate decision making when managing these challenging vascular malformations. The mean age at presentation was 42 years without a sex predilection. Thirty-eight percent of the cases were cervical, 57% thoracic, 4% lumbar, and 1% unspecified location. Nine percent of the patients had a family history of CNS CMs. Twenty-seven percent of the patients had an associated cranial CM. On presentation 63% of the patients had motor deficits, 65% had sensory deficits, 27% had pain, and 11% had bowel or bladder dysfunction. Presentation was acute in 30%, recurrent in 16%, and progressive in 54% of cases. An overall annual hemorrhage rate was calculated as 2.5% for 92 patients followed up for a total of 2571 patient-years. Across 24 reviewed surgical series, a 91% complete resection rate was found. Transient morbidity was seen in 36% of cases. Sixty-one percent of patients improved, 27% were unchanged, and 12% were worse at the long-term follow-up. Using this information, the authors review surgical nuances in treating these lesions and propose a management algorithm.