Extensive calcification of the ligamentum flavum causing cervical myelopathy in a Caucasian woman

textabstractCalcification of the ligamentum flavum (CLF) can cause myelopathy due to spinal cord compression. Only several cases in Caucasian patients have been described. Neurological deterioration can only be stopped by surgical decompression. We report a 63-year-old Caucasian woman presenting with progressive pins-and-needles sensations in both hands, worsened by painful paresthesia in both lower extremities. MRI showed a dorsal compressive mass extending from C2 to Th3 vertebrae with myelopathy at the level of C6. A laminectomy was performed, which improved clinical symptoms. Histological examination showed CLF. Early recognition of CLF and early spinal cord decompression are needed to improve neurological outcome

Brain parenchyma/p02 catheter interface:A histopathological study in the Rat

Local cerebral oxygénation can be monitored continuously using an intraparenchymal Clark-typePO2 sensitive catheter. Measured values of brain tissue p02 (Pbr02) not only depend on the clinically interesting balance between oxygen offer and demand, but also on catheter properties andcharacteristics of the probe tissue interface. Microdamage surrounding p02-sensitive needles, inserted into various tissues, has been reported; we evaluated histologie changes at the probe tissueinterface after insertion of p()2 probes, suitable for clinical use, in the rat brain. The effect of insertion of the probe itself (mechanical damage), the application of micropotential during the measurements, and the effect of time was evaluated using digital image analysis of H&E-stained histológica! slices. Surrounding the probe tract, a zone of edema with an average radius of 126.8 /im wasseen; microhemorrhages with an average surface area of 56.2 X 103 fim2 were observed in nearlyall cases. The area of edema and the presence of microhemorrhages were not influenced by performed measurements or by time. Intraventricular blood was observed in 10 of 19 rats studied. Measured low Pbr02 values were related to the presence of a microhemorrhage in either probe tract orventricles. Tissue damage due to the measurements is negligible, and the amount of edema itselfdoes not influence the accuracy or response time of the p02 probe. Low Pbr02 readings, however,could be caused by local microhemorrhages, undetectable on CT or MRI

Brain parenchyma/p02 catheter interface:A histopathological study in the Rat

Local cerebral oxygénation can be monitored continuously using an intraparenchymal Clark-typePO2 sensitive catheter. Measured values of brain tissue p02 (Pbr02) not only depend on the clinically interesting balance between oxygen offer and demand, but also on catheter properties andcharacteristics of the probe tissue interface. Microdamage surrounding p02-sensitive needles, inserted into various tissues, has been reported; we evaluated histologie changes at the probe tissueinterface after insertion of p()2 probes, suitable for clinical use, in the rat brain. The effect of insertion of the probe itself (mechanical damage), the application of micropotential during the measurements, and the effect of time was evaluated using digital image analysis of H&E-stained histológica! slices. Surrounding the probe tract, a zone of edema with an average radius of 126.8 /im wasseen; microhemorrhages with an average surface area of 56.2 X 103 fim2 were observed in nearlyall cases. The area of edema and the presence of microhemorrhages were not influenced by performed measurements or by time. Intraventricular blood was observed in 10 of 19 rats studied. Measured low Pbr02 values were related to the presence of a microhemorrhage in either probe tract orventricles. Tissue damage due to the measurements is negligible, and the amount of edema itselfdoes not influence the accuracy or response time of the p02 probe. Low Pbr02 readings, however,could be caused by local microhemorrhages, undetectable on CT or MRI

A unified 3D map of microscopic architecture and MRI of the human brain

We present the first three-dimensional (3D) concordance maps of cyto- and fiber architecture of the human brain, combining histology, immunohistochemistry, and 7-T quantitative magnetic resonance imaging (MRI), in two individual specimens. These 3D maps each integrate data from approximately 800 microscopy sections per brain, showing neuronal and glial cell bodies, nerve fibers, and interneuronal populations, as well as ultrahigh-field quantitative MRI, all coaligned at the 200-μm scale to the stacked blockface images obtained during sectioning. These unprecedented 3D multimodal datasets are shared without any restrictions and provide a unique resource for the joint study of cell and fiber architecture of the brain, detailed anatomical atlasing, or modeling of the microscopic underpinnings of MRI contrasts

A unified 3D map of microscopic architecture and MRI of the human brain

We present the first three-dimensional (3D) concordance maps of cyto- and fiber architecture of the human brain, combining histology, immunohistochemistry, and 7-T quantitative magnetic resonance imaging (MRI), in two individual specimens. These 3D maps each integrate data from approximately 800 microscopy sections per brain, showing neuronal and glial cell bodies, nerve fibers, and interneuronal populations, as well as ultrahigh-field quantitative MRI, all coaligned at the 200-μm scale to the stacked blockface images obtained during sectioning. These unprecedented 3D multimodal datasets are shared without any restrictions and provide a unique resource for the joint study of cell and fiber architecture of the brain, detailed anatomical atlasing, or modeling of the microscopic underpinnings of MRI contrasts

DataSheet_1_Bet v 1-displaying elastin-like polypeptide nanoparticles induce a strong humoral and weak CD4+ T-cell response against Bet v 1 in a murine immunogenicity model.docx

There is growing concern about the toxicity of colloidal aluminum salts used as adjuvants in subcutaneous allergen immunotherapy (SCIT). Therefore, alternative adjuvants and delivery systems are being explored to replace alum in SCIT. We applied micellar elastin-like polypeptides (ELPs), a type of self-assembling protein, to replace alum as vaccine adjuvant in birch pollen SCIT. ELP and an ELP-Bet v 1 fusion protein were expressed in E. coli and purified by immuno-affinity chromatography and inverse-transition cycling (ITC). Nanoparticles self-assembled from ELP and a 9:1 ELP/ELP-Bet v 1 mixture were characterized by using dynamic light scattering and atomic force microscopy. Allergenicity was assessed by measuring mediator release from rat basophilic leukemia cells transformed with the human FcϵR1 and sensitized with sera derived from human birch pollen allergic patients. Humoral and T-cell immunity were investigated by immunizing naïve mice with the ELP/ELP-Bet v 1 nanoparticles or alum-adsorbed Bet v 1, both containing 36 µg Bet v 1. ELP and ELP/ELP-Bet v 1 self-assembled at 37°C into spherically shaped micelles with a diameter of ~45 nm. ELP conjugation made Bet v 1 hypo-allergenic (10-fold). Compared to alum-adsorbed Bet v 1, ELP/ELP-Bet v 1 nanoparticles induced stronger IgG responses with an earlier onset. Additionally, ELP/ELP-Bet v 1 did not induce Th2 skewing cytokines and IgE. The hypoallergenic character and strong humoral immune response in the absence of a Th2-skewing T-cell response make ELP-based nanoparticles a promising candidate to replace alum in SCIT.</p

EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology

Over the past decade a series of trials of the EORTC Brain Tumor Group (BTG) has substantially influenced and shaped the standard-of-care of primary brain tumors. All these trials were coupled with biological research that has allowed for better understanding of the biology of these tumors. In glioblastoma, EORTC trial 26981/22981 conducted jointly with the National Cancer Institute of Canada Clinical Trials Group showed superiority of concomitant radiochemotherapy with temozolomide over radiotherapy alone. It also identified the first predictive marker for benefit from alkylating agent chemotherapy in glioblastoma, the methylation of the O6-methyl-guanyl-methly-transferase (MGMT) gene promoter. In another large randomized trial, EORTC 26951, adjuvant chemotherapy in anaplastic oligodendroglial tumors was investigated. Despite an improvement in progression-free survival this did not translate into a survival benefit. The third example of a landmark trial is the EORTC 22845 trial. This trial led by the EORTC Radiation Oncology Group forms the basis for an expectative approach to patients with low-grade glioma, as early radiotherapy indeed prolongs time to tumor progression but with no benefit in overall survival. This trial is the key reference in deciding at what time in their disease adult patients with low-grade glioma should be irradiated. Future initiatives will continue to focus on the conduct of controlled trials, rational academic drug development as well as systematic evaluation of tumor tissue including biomarker development for personalized therapy. Important lessons learned in neurooncology are to dare to ask real questions rather than merely rapidly testing new compounds, and the value of well designed trials, including the presence of controls, central pathology review, strict radiology protocols and biobanking. Structurally, the EORTC BTG has evolved into a multidisciplinary group with strong transatlantic alliances. It has contributed to the maturation of neurooncology within the oncological sciences

Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma.

PURPOSE: Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. PATIENTS AND METHODS: We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. RESULTS: TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P &lt; .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P &lt; .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P &lt; .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. CONCLUSION: Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients

Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma

Purpose Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. Patients and Methods We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. Results TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. Conclusion Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients