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In this study, topology optimized, patient specific osteosynthesis plates (TOPOS-implants) are evaluated for the mandibular reconstruction using fibula segments. These shape optimized implants are compared to a standard treatment with miniplates (thickness: 1.0 mm, titanium grade 4) in biomechanical testing using human cadaveric specimen. Mandible and fibula of 21 body donors were used. Geometrical models were created based on automated segmentation of CT-scans of all specimens. All reconstructions, including cutting guides for osteotomy as well as TOPOS-implants, were planned using a custom-made software tool. The TOPOS-implants were produced by electron beam melting (thickness: 1.0 mm, titanium grade 5). The fibula-reconstructed mandibles were tested in static and dynamic testing in a multi-axial test system, which can adapt to the donor anatomy and apply side-specific loads. Static testing was used to confirm mechanical similarity between the reconstruction groups. Force-controlled dynamic testing was performed with a sinusoidal loading between 60 and 240 N (reconstructed side: 30% reduction to consider resected muscles) at 5 Hz for up to 5 · 105 cycles. There was a significant difference between the groups for dynamic testing: All TOPOS-implants stayed intact during all cycles, while miniplate failure occurred after 26.4% of the planned loading (1.32 · 105 ± 1.46 · 105 cycles). Bone fracture occurred in both groups (miniplates: n = 3, TOPOS-implants: n = 2). A correlation between bone failure and cortical bone thickness in mandible angle as well as the number of bicortical screws used was demonstrated. For both groups no screw failure was detected. In conclusion, the topology optimized, patient specific implants showed superior fatigue properties compared to miniplates in mandibular reconstruction. Additionally, the patient specific shape comes with intrinsic guiding properties to support the reconstruction process during surgery. This demonstrates that the combination of additive manufacturing and topology optimization can be beneficial for future maxillofacial surgery.

Surgical sutures can promote migration of bacteria and thus start infections. Antiseptic coating of sutures may inhibit proliferation of adhered bacteria and avoid such complications.This study investigated the inhibition of viable adhering bacteria on novel antimicrobially coated surgical sutures using chlorhexidine or octenidine, a critical factor for proliferation at the onset of local infections. The medical need, a rapid eradication of bacteria in wounds, can be fulfilled by a high antimicrobial efficacy during the first days after wound closure.As a pretesting on antibacterial efficacy against relevant bacterial pathogens a zone of inhibition assay was conducted with middle ranged concentrated suture coatings (22 μg/cm). For further investigation of adhering bacteria in detail the most clinically relevant Staphylococcus aureus (ATCC®49230™) was used. Absorbable braided sutures were coated with chlorhexidine-laurate, chlorhexidine-palmitate, octenidine-laurate, and octenidine-palmitate. Each coating type resulted in 11, 22, or 33 μg/cm drug content on sutures. Scanning electron microscopy (SEM) was performed once to inspect the coating quality and twice to investigate if bacteria have colonized on sutures. Adhesion experiments were assessed by exposing coated sutures to S. aureus suspensions for 3 h at 37°C. Subsequently, sutures were sonicated and the number of viable bacteria released from the suture surface was determined. Furthermore, the number of viable planktonic bacteria was measured in suspensions containing antimicrobial sutures. Commercially available sutures without drugs (Vicryl®, PGA Resorba®, and Gunze PGA), as well as triclosan-containing Vicryl® Plus were used as control groups.Zone of inhibition assay documented a multispecies efficacy of novel coated sutures against tested bacterial strains, comparable to most relevant S. aureus over 48 hours. SEM pictures demonstrated uniform layers on coated sutures with higher roughness for palmitate coatings and sustaining integrity of coated sutures. Adherent S. aureus were found via SEM on all types of investigated sutures. The novel antimicrobial sutures showed significantly less viable adhered S. aureus bacteria (up to 6.1 log) compared to Vicryl® Plus (0.5 log). Within 11 μg/cm drug-containing sutures, octenidine-palmitate (OL11) showed the highest number of viable adhered S. aureus (0.5 log), similar to Vicryl® Plus. Chlorhexidine-laurate (CL11) showed the lowest number of S. aureus on sutures (1.7 log), a 1.2 log greater reduction. In addition, planktonic S. aureus in suspensions were highly inhibited by CL11 (0.9 log) represents a 0.6 log greater reduction compared to Vicryl® Plus (0.3 log).Novel antimicrobial sutures can potentially limit surgical site infections caused by multiple pathogenic bacterial species. Therefore, a potential inhibition of multispecies biofilm formation is assumed. In detail tested with S. aureus, the chlorhexidine-laurate coating (CL11) best meets the medical requirements for a fast bacterial eradication. This suture coating shows the lowest survival rate of adhering as well as planktonic bacteria, a high drug release during the first-clinically most relevant- 48 hours, as well as biocompatibility. Thus, CL11 coatings should be recommended for prophylactic antimicrobial sutures as an optimal surgical supplement to reduce wound infections. However, animal and clinical investigations are important to prove safety and efficacy for future applications.

[This corrects the article DOI: 10.1371/journal.pone.0190912.].

BACKGROUND:Frame-based stereotactic biopsy (FBSB) is a minimally-invasive and effective procedure for the diagnosis of brain lesions and will likely gain clinical importance. Since FBSB procedures comprise a variety of imaging and sampling methods, it is necessary to compare the safety and effectiveness of individual techniques. OBJECTIVE:To assess the safety and effectiveness of FBSB using 1.5T iMRI as a one-stop procedure under general anesthesia without intraoperative histological examination. METHODS:In this single-center, retrospective analysis, 500 consecutive FBSBs using iMRI were compared to a historic control of 100 biopsies with traditional workflows (computed tomography (CT) with MRI image fusion). All procedures were performed under general anesthesia. Data on surgical procedures, pre- and postoperative neurologic patient status, complications and diagnostic yield were extracted from clinical records. RESULTS:Complication rates and diagnostic yield showed no significant differences between both groups. Mortality was 0.6%, 95% CI = [0.12%, 1.74%], in the iMRI and 0.0% [0.00%, 3.62%], in the control group with a morbidity of 5.4% [3.6%, 7.8%] and 6.0% [2.2%, 12.6%] and a diagnostic yield of 96.8% [94.9%, 98.2%] and 96.0% [90.1%, 98.9%]. Mean procedure duration was 124 [121, 127] minutes using iMRI and 112 [106, 118] minutes in the control group. CONCLUSION:FBSB using 1.5T iMRI under general anesthesia is a safe and effective procedure and is equivalent to traditional stereotactic workflows with respect to complication rate and diagnostic yield.

Interfaces between tendon/ligament and bone ("entheses") are highly specialized tissues that allow for stress transfer between mechanically dissimilar materials. Entheses show very low regenerative capacity resulting in high incidences of failure after surgical repair. Tissue engineering is a promising approach to recover functionality of entheses. Here, we established a protocol to decellularize porcine entheses as scaffolds for enthesis tissue engineering. Chemical detergents as well as physical treatments were investigated with regard to their efficiency to decellularize 2 mm thick porcine Achilles tendon entheses. A two-phase approach was employed: study 1 investigated the effect of various concentrations of sodium dodecyl sulfate (SDS) and t-octylphenoxypolyethoxy-ethanol (Triton X-100) as decellularization agents. The most efficient combination of SDS and Triton was then carried forward into study 2, where different physical methods, including freeze-thaw cycles, ultrasound, perfusion, and hydrostatic washing were used to enhance the decellularization effect. Cell counts, DNA quantification, and histology showed that washing with 0.5% SDS + 1% Triton X-100 for 72 h at room temperature could remove ~ 98% cells from the interface. Further investigation of physical methods proved that washing under 200 mmHg hydrostatic pressure shortened the detergent exposing time from 72 h to 48 h. Biomechanical tensile testing showed that the biomechanical features of treated samples were preserved. Washing under 200 mmHg hydrostatic pressure with 0.5% SDS + 1% Triton X-100 for 48 h efficiently decellularized entheses with preservation of matrix structure and biomechanical features. This protocol can be used to efficiently decellularize entheses as scaffolds for tissue engineering.

INTRODUCTION: Visual but subjective reading of longitudinal relaxation time (T1) weighted magnetic resonance images is commonly used for the detection of brain pathologies. For this non-quantitative measure, diagnostic quality depends on hardware configuration, imaging parameters, radio frequency transmission field (B1+) uniformity, as well as observer experience. Parametric quantification of the tissue T1 relaxation parameter offsets the propensity for these effects, but is typically time consuming. For this reason, this study examines the feasibility of rapid 2D T1 quantification using a variable flip angles (VFA) approach at magnetic field strengths of 1.5 Tesla, 3 Tesla, and 7 Tesla. These efforts include validation in phantom experiments and application for brain T1 mapping. METHODS: T1 quantification included simulations of the Bloch equations to correct for slice profile imperfections, and a correction for B1+. Fast gradient echo acquisitions were conducted using three adjusted flip angles for the proposed T1 quantification approach that was benchmarked against slice profile uncorrected 2D VFA and an inversion-recovery spin-echo based reference method. Brain T1 mapping was performed in six healthy subjects, one multiple sclerosis patient, and one stroke patient. RESULTS: Phantom experiments showed a mean T1 estimation error of (-63±1.5)% for slice profile uncorrected 2D VFA and (0.2±1.4)% for the proposed approach compared to the reference method. Scan time for single slice T1 mapping including B1+ mapping could be reduced to 5 seconds using an in-plane resolution of (2×2) mm2, which equals a scan time reduction of more than 99% compared to the reference method. CONCLUSION: Our results demonstrate that rapid 2D T1 quantification using a variable flip angle approach is feasible at 1.5T/3T/7T. It represents a valuable alternative for rapid T1 mapping due to the gain in speed versus conventional approaches. This progress may serve to enhance the capabilities of parametric MR based lesion detection and brain tissue characterization.

The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies.

Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in NBN or ATM result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show in vivo consequences of conditional inactivation of both genes in neural stem/progenitor cells using Nestin-Cre mice. Genetic inactivation of Atm in the central nervous system of Nbn-deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with Nbn deletion was prevented by simultaneous inactivation of Atm in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner.

Malignant peripheral nerve sheath tumor (MPNST) is a rare aggressive form of sarcoma often associated with the tumor syndrome neurofibromatosis type 1 (NF1). We investigated the effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on NF1 associated MPNST and determinants of TRAIL sensitivity. MPNST cell lines with complete neurofibromin deficiency were sensitive to apoptotic cell death induced by TRAIL whereas MPNST cells with retained neurofibromin expression or normal human Schwann cells were resistant. Increased sensitivity to TRAIL was associated with overexpression of death receptors, especially DR5. Re-expression of the GAP related domain of neurofibromin (NF1-GRD) suppressed DR5 expression and decreased sensitivity to TRAIL. We show that death receptor expression and TRAIL sensitivity critically depend on c-MYC and that c-MYC amounts are increased by MEK/ERK and PI3K/AKT signalling pathways which are suppressed by neurofibromin. Furthermore PI3K/AKT signalling strongly suppresses the MYC-antagonist MAD1 which significantly contributes to TRAIL sensitivity. Re-expression of the NF1-GRD decreased c-MYC and increased MAD1 amounts suggesting that neurofibromin influences TRAIL sensitivity at least in part by modulating the MYC/MAX/MAD network. The phytochemical curcumin further increased the sensitivity of neurofibromin deficient MPNST cells to TRAIL. This was presumably mediated by ROS, as it correlated with increased ROS production, was blocked by N-acetylcysteine and mimicked by exogenous ROS.

Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O(6)-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide. Hence, the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma. Since various different techniques are available for MGMT promoter methylation analysis, a generally accepted consensus as to the most suitable diagnostic method remains an unmet need. Here, we assessed methylation-specific polymerase chain reaction (MSP) as a qualitative and semi-quantitative method, pyrosequencing (PSQ) as a quantitative method, and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a semi-quantitative method in a series of 35 formalin-fixed, paraffin-embedded glioblastoma tissues derived from patients treated in a prospective clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide (UKT-05). Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival (PFS). The MGMT promoter methylation status was assessable by each method in almost all cases (n = 33/35 for MSP; n = 35/35 for PSQ; n = 34/35 for MS-MLPA). We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ (range, 11.5 to 44.9%) and at one CpG site assessed by MS-MLPA (3.6%) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible. Our results show that, unlike MS-MLPA, MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone (likelihood ratio tests: p

BACKGROUND: To investigate the dynamics of inter- and intratumoral molecular alterations during tumor progression in recurrent gliomas. METHODOLOGY/PRINCIPAL FINDINGS: To address intertumoral heterogeneity we investigated non-microdissected tumor tissue of 106 gliomas representing 51 recurrent tumors. To address intratumoral heterogeneity a set of 16 gliomas representing 7 tumor pairs with at least one recurrence, and 4 single mixed gliomas were investigated by microdissection of distinct oligodendroglial and astrocytic tumor components. All tumors and tumor components were analyzed for allelic loss of 1p/19q (LOH 1p/19q), for TP53- mutations and for R132 mutations in the IDH1 gene. The investigation of non-microdissected tumor tissue revealed clonality in 75% (38/51). Aberrant molecular alterations upon recurrence were detected in 25% (13/51). 64% (9/14) of these were novel and associated with tumor progression. Loss of previously detected alterations was observed in 36% (5/14). One tumor pair (1/14; 7%) was significant for both. Intratumoral clonality was detected in 57% (4/7) of the microdissected tumor pairs and in 75% (3/4) of single microdissected tumors. 43% (3/7) of tumor pairs and one single tumor (25%) revealed intratumoral heterogeneity. While intratumoral heterogeneity affected both the TP53- mutational status and the LOH1p/19q status, all tumors with intratumoral heterogeneity shared the R132 IDH1- mutation as a common feature in both their microdissected components. CONCLUSIONS/SIGNIFICANCE: The majority of recurrent gliomas are of monoclonal origin. However, the detection of divertive tumor cell clones in morphological distinct tumor components sharing IDH1- mutations as early event may provide insight into the tumorigenesis of true mixed gliomas.

Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n=16) than in neurofibromas (n=16) and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n=31) and PIK3CA (n=38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1-/- and NF1+/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms.

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that epigenetically silences gene transcription through histone H3 lysine trimethylation (H3K27me3). EZH2 has been implicated in stem cell maintenance and is overexpressed in hematological and solid malignancie`s including malignant glioma. EZH2 is thought to promote tumor progression by silencing tumor suppressor genes. Hence pharmacological disruption of the PRC2 is an attractive therapeutic strategy for cancer treatment. Here we show that EZH2 is expressed in human glioma and correlates with malignancy. Silencing of EZH2 reduced glioma cell proliferation and invasiveness. While we did not observe induction of cell cycle-associated tumor suppressor genes by silencing or pharmacological inhibition of EZH2, microarray analyses demonstrated a strong transcriptional reduction of the AXL receptor kinase. Neither histone nor DNA methylation appeared to be involved in the positive regulation of AXL by EZH2. Silencing AXL mimicked the antiinvasive effects of EZH2 knockdown. Finally, AXL expression is found in human gliomas with high EZH2 expression. Collectively these data suggest that EZH2 drives glioma invasiveness via transcriptional control of AXL independent of histone or DNA methylation.

The INhibitor of Growth tumor suppressors (ING1-ING5) affect aging, apoptosis, DNA repair and tumorigenesis. Plant homeodomains (PHD) of ING proteins bind histones in a methylation-sensitive manner to regulate chromatin structure. ING1 and ING2 contain a polybasic region (PBR) adjacent to their PHDs that binds stress-inducible phosphatidylinositol monophosphate (PtIn-MP) signaling lipids to activate these INGs. ING1 induces apoptosis independently of p53 but other studies suggest proapoptotic interdependence of ING1 and p53 leaving their functional relationship unclear. Here we identify a novel ubiquitin-binding domain (UBD) that overlaps with the PBR of ING1 and shows similarity to previously described UBDs involved in DNA damage responses. The ING1 UBD binds ubiquitin with high affinity (K(d)∼100 nM) and ubiquitin competes with PtIn-MPs for ING1 binding. ING1 expression stabilized wild-type, but not mutant p53 in an MDM2-independent manner and knockdown of endogenous ING1 depressed p53 levels in a transcription-independent manner. ING1 stabilized unmodified and six multimonoubiquitinated forms of wild-type p53 that were also seen upon DNA damage, but not p53 mutants lacking the six known sites of ubiquitination. We also find that ING1 physically interacts with herpesvirus-associated ubiquitin-specific protease (HAUSP), a p53 and MDM2 deubiquitinase (DUB), and knockdown of HAUSP blocks the ability of ING1 to stabilize p53. These data link lipid stress signaling to ubiquitin-mediated proteasomal degradation through the PBR/UBD of ING1 and further indicate that ING1 stabilizes p53 by inhibiting polyubiquitination of multimonoubiquitinated forms via interaction with and colocalization of the HAUSP-deubiquitinase with p53.

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive tumors which originate from Schwann cells and develop in about 10% of neurofibromatosis type 1 (NF1) patients. The five year survival rate is poor and more effective therapies are needed. Sunitinib is a drug targeting receptor tyrosine kinases (RTK) like PDGFRalpha, c-Kit and VEGFR-2. These genes are structurally related and cluster on chromosomal segment 4q12.Here we characterize this region by multiplex ligation-dependent probe amplification (MLPA) in MPNST. Our probe set encompasses the 3 adjacent RTK genes (PDGFRA, KIT, KDR) and 6 flanking genes. We found amplification of several genes within this region in a subset of MPNST and MPNST cell lines. Transcript and protein expression of PDGFRA matched well with its increased copy number suggesting a central role of PDGFRA within the amplicon. Studying the effect of sunitinib on 5 MPNST cell lines revealed that cell line S462 harboring the 4q12 amplicon was extremely sensitive to the drug with an IC50 below 1.0 microM. Moreover, sunitinib induced apoptosis and prevented PDGF-AA induced signaling via PDGFRalpha as determined by western blotting. Co-expression of VEGF and its receptor VEGFR-2 (KDR) was present in MPNST cell lines suggesting an autocrine loop. We show that VEGF triggered signal transduction via the MAPK pathway, which could be blocked by sunitinib.Since multiple receptors targeted by sunitinib are expressed or over-expressed by MPNST cells sunitinib appears as an attractive drug for treatment of MPNST patients. Presence of the 4q12 amplicon and subsequent over-expression of PDGFRA might serve as predictive markers for efficacy of sunitinib.

Introduction: Visual but subjective reading of longitudinal relaxation time (T1) weighted magnetic resonance images is commonly used for the detection of brain pathologies. For this non-quantitative measure, diagnostic quality depends on hardware configuration, imaging parameters, radio frequency transmission field (B1+) uniformity, as well as observer experience. Parametric quantification of the tissue T1 relaxation parameter offsets the propensity for these effects, but is typically time consuming. For this reason, this study examines the feasibility of rapid 2D T1 quantification using a variable flip angles (VFA) approach at magnetic field strengths of 1.5 Tesla, 3 Tesla, and 7 Tesla. These efforts include validation in phantom experiments and application for brain T1 mapping. Methods: T1 quantification included simulations of the Bloch equations to correct for slice profile imperfections, and a correction for B1+. Fast gradient echo acquisitions were conducted using three adjusted flip angles for the proposed T1 quantification approach that was benchmarked against slice profile uncorrected 2D VFA and an inversion-recovery spin-echo based reference method. Brain T1 mapping was performed in six healthy subjects, one multiple sclerosis patient, and one stroke patient. Results: Phantom experiments showed a mean T1 estimation error of (-63±1.5)% for slice profile uncorrected 2D VFA and (0.2±1.4)% for the proposed approach compared to the reference method. Scan time for single slice T1 mapping including B1+ mapping could be reduced to 5 seconds using an in-plane resolution of (2×2) mm2, which equals a scan time reduction of more than 99% compared to the reference method. Conclusion: Our results demonstrate that rapid 2D T1 quantification using a variable flip angle approach is feasible at 1.5T/3T/7T. It represents a valuable alternative for rapid T1 mapping due to the gain in speed versus conventional approaches. This progress may serve to enhance the capabilities of parametric MR based lesion detection and brain tissue characterization. [ABSTRACT FROM AUTHOR]

The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies. [ABSTRACT FROM AUTHOR]

Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment. [ABSTRACT FROM AUTHOR]

Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment. [ABSTRACT FROM AUTHOR]